PL163045B1 - Method of obtaining novel derivatives of 1,3-dioxane-alkenic acid - Google Patents

Abstract

The invention concerns novel, pharmaceutically useful 1,3-dioxane alkenoic acid derivatives of the formula I containing a pyridyl moiety at position 4 of the dioxane ring and in which the groups at positions 2, 4 and 5 have cis-relative stereochemistry, X is hydrogen, alkoxy or hydroxy, Y is vinylene, n is 1 or 2, A<1> is alkylene, the substituents R<1> and R<2> at position 2 of the dioxane ring have a variety of values defined hereinafter, and R<4> is hydroxy, a physiologically acceptable alcohol residue or alkanesulphonamido, and the pharmaceutically acceptable salts thereof. The invention also includes processes for the manufacture and use of the acid derivatives as well as pharmaceutical compositions for therapeutic use in one or more of a variety of diseases such as ischaemic heart disease, cerebrovascular disease, asthmatic disease and/or inflammatory disease. <CHEM> l

Description

The subject of the invention is a process for the preparation of novel 1,3-dloxaelklaic acid derivatives, in particular 1,3-dgokβaa-5-ygaalkanoic acid derivatives ^^ ιπ ^ ου ^ SlΓydygoo group variable in the 4-position of the 1,3-dgok8anum ring. The acids according to the invention are of great pharmaceutical nature and are suitable for the production of pharmaceutical agents.

It is known that Mlaboglk of lrachldonool acid, ^^ boxm A2 / hereinafter referred to as * · ₂ · /, quadruples a strong vasoconstrictor factor and a strong factor purchased platelets. TXA ₂ is also a strong zoιerwcr dskrzegowlgd and tracheal smooth muscle. TX> 2 may be associated with disease-related melon, e.g. with ischemic heart disease, such as myocardial infarction, angina pectoris, cardiovascular disease, and so on. Such as transient brain disease, migraine and stroke, peripheral vascular disease such as hardening of the arteries, sore throat, hyperthyroidism, water caused by blood clotting caused by July imbalance.

It is believed that its action TXAg aviary fizoooogcczne receptor-krombokswau, where I ^^ iarzć contractile action also various other substances prdstenoldooe of ołzścioościzch shrink ^ come from erachldonowlgo acid such as srdstzglandnny ^h 2 * 2 ^ al ^ ¹ and Di proztzglandnnz . There are two main ways to reduce the effects of ΤΧΑ2 · Foot is to administer a pharmacological agent that first binds to the boxm receptor, bad Yet does not cause exudative contractility effects after choking ΤΧΑ2 / Jo srozkeglanlyn H2 »F2 al ^ia i / uuD O2 / · The kailm middle is said to have ankagdnlistic properties towards wobec2. The second method consists in administering a famacoglycemic agent which inhibits one or the tormenting enzymes involved in the production of ΤΧΑ2, with zisrjza which inhibits the enzyme which depletes the synthesis of thrombdosis / synt2 synthesis /. Such a medium is said to be and μι ^ ηοιοι in the synthesis of ΤΧΑ2.

From the above, it can be seen that agents that have antagonistic properties to ΤΧΑ2 1 which inhibit the synthesis of ΤΧΑ2 »should have a weight loss in one or more of the above-mentioned diseases or other diseases with which TXA is associated? .. It can also be expected that Agents with tagonic properties towards ΤΧΛ-, will have ιοζ-ιι- in addition to the treatment of those diseases with which prdzkl3lendyay ł ^, Fg alpha and / uub D ”are related, e.g.

163 045 especially asthmatic and inflammatory diseases. Although 1,3-dioxane compounds are known. As anti-chasing TKAj / e.g. described in European Patent No. 9423B1 and / known that certain inhibitors of the synthesis of TXA ₂ / ⁿ p. European Patent Application No. 9869C0A2 /, to obtain compounds.

which would combine both features and a small broad utility, is not easy.

It has been found / and this is the basis of the present invention /. with certain 1,3-dioxane-5-ylacknic acids of formula 1. containing a pyridyl group bound at the base of the 1,3-dioxane ring. unexpectedly, they are good inhibitors of TXA synthesis and they also have significant antagonistic properties towards TXAg 1 and are suitable for use as pharmaceuticals.

The process according to the invention provides a 1,3-dloalkanoic acid derivative of formula 1. wherein n is an integer 1 or /. X is hydrogen. hydroxyl or / - CC / β11oxy. Y is a methylanoxy group. vinylene or ethylene. represents the group [alpha] -6CC, [beta] alkyl. and furthermore a / R is hydrogen. R is a naphthyl group. optionally containing 1 or / substituents.

such as a halogen atom. cyano group. nitro. / 1-C / alkHowa /. / - 4C / alnok8ynowa or 1 3/3 tnflunromθtylnwa. or R is a group of formula R A -, wherein R is phenyl. substituted eem substituent such as a / - C / alkyl group. / - CC / eHoka yoowa. hydroxyl. (2-iC) alkenyl. / l-4C / elk 1I0110. / - C / akkHoaulfindium. / - CC / akkllouulniπyl. / 2-5C / akkanoyl. carboxylic acid. / / 1-CC / all10ny_7carnonylα, NN- / 1-4C / alkylT / ka kaaHowa. / l-cc / alkyneolommtnowα or / l-c / alkali. substituted with the group / l-C: / alnocoyl. cyan. carboxylic acid; and the phenyl group may have a second substituent. such as a (1-C) alkUo group. / - C // llnlkβylooα. triflunrnnetnlooe. nitro. cyano or halogen. or R is an alyl or furyl group. optionally a substituent of 1 or two substituents independently selected from the group consisting of /

halogen. the / 1-C / βkklowy group. nitrous. 1 cyan. A is a (-6C) alkyl alcohol group.

oxy / 1-6C / alkyl or / 2-6C / 8lkβπykθπowy. with up to three carbon atoms of each. / groups may be wholly or partially fluorinated. or A stands for direct imprisonment

1 2 3 1 12 from R. or R is a group of the formula Q.A.Q -, wherein Q 1 Q are aromatic groups. One is benzene. the other is benzene or pyridine. each of these groups may be optionally substituted with a cnlomca atom. cyano group. nitrous. / l-C / aiklin.

/ - 4CkθlllS8yl or t? Uoromethyl. and A is tu, sulfmoyl. oulfoinloo.

carbonyl. larbomoylnoea. carbohydrate name. ureid. (16) (alkali). ok8ynl-6CCelkilk1 2 new. / 266C / alknnyeinooιę or direct linkage between Q and Q.

10 / R denotes the pantaflJornethylooa group. and R is hydrogen. or each of R p

R * represents a t rff locumethyl group. either 1 2 c / R and R independently represent an alkyl group or together I form an alkleyl group like this. that R &lt; 1 &gt; and R &lt; 4 &gt; together contain 5-9 carbon atoms. R ^- represents ru ^{g PE} ^ drnlksylowę. ^f ^ lzjo cally ^d opuazczalne alcohol residue or a / l-CC / 8lkenouunfonamlnowę or pharmaceutically acceptable salts thereof.

It should be noted. from the compound of formula I, I have asymmetric carbon atoms, and can exist and be isolated in racial and optically active forms. The invention relates to the preparation of both the racemic forms. as 1 optically active / uub their mlθszanin /. which are capable of antagonizing One or more of the actions of the TKA / 1 inhibitor of TXA synthesis /. well known. how are individual optical isomers prepared / e.g. by synthesis from optically active starting materials or by cleavage of racamic forms /. and How the TKAg antagnlotic properties and TXA synthesis properties are determined using one or more standard tests. described p ^ nn ^^ j.

Should be understood. from the group in positions - 1 5 / and also in zitu 2. when R is hydrogen / the 1.3-dllOsnn groups in formula 1 have a relative constant ^ ΐ9 (: ^ (^ ήβϋς cis. as groups adjacent to the vinylate group Y / i.e. these the last compounds exist as the Z / isomer. Moreover, although a specific configuration is given in the attached formulas Jnkm.JziyJn, it does not have to correspond to the absolute configuration

It should also be understood. the term alllkin group ° includes straight and branched chain groups. such as the ethylene group and the group of names other names are constructed after 163,045 to the Day. However, a name such as Yak is appropriate for a straight chain or "normal chain" butyl group, such as t-butyl, will be specifically specified if necessary.

2

When R and R denote an alkyl group, it is e.g. aaeyl, ethyl, propyl, isopropyl, butyl and pantyl group, and when together I form an alkUnno group it is e.g. a tetheamethylate, pentamethylene and hexaaeeylene group, each of them it may contain 1 or 2 mθJyiooe substituents.

When R is enylot ^f lo / ll: C / ^l alkl ^these, it is, for instance. ^G roup atylo l- ^m-l - / ^ nylotio / or atyoowa fenylotlOletylooa, ewenlt ^ el.nle substituted as described above.

Substituents ^k t ^yellow re eoenluallle can zawl.Jrac ^{r1 g} d ^y is the ^g ^ roup ^ę Natta hose l.ub phenyl1 background 2 / -66C / alkllowę, aioo aromatic moiety Q people Defined ^ Q ^ may powyżae ane, can be, for example. : as a group / ^ cc / alkiowi '! methyl and ethyl group. As a <1> -1alllxyl group, methoxy and ethoxy, as a halogen atom: fluorine, chlorine and bromine.

When X is an alkoxy group, it is, for example, an acetoxy or ethoxy group. about

The substituents which R may contain when it represents a phenyl, thianyo or furoyl group may be, for example: as a (-44C) (8) methyl and ethyl group, as a (cc) ackoxy group, aeJoxylooa and Jtlxylooa groups, as a halogen halogen, chlorine and bromine as a (2-5C) allJnylo vinyl group, 2-propylloyl, and 3,3-forI44C) alkylthio group (meyrio, and Jtyllthio as a (14CC) alkylsulfmy methylsulfinyl group and ethy llsulflnyl as group / l4C; / ackylouulfltyl group meeylsulphonyl and ethyloullonyloo. As group / 2-5C / allanoyl group, acetyl, propionyl, butyryl and 2-oxopropyl, as group / ^- / l-4C / alkoxy_7larαyljoylooa group -butolsyclrbnyl, As / lN- / l4c; / ekillo_7carbmmol group N-meJylcarbmollooa, N-ethylcarbmollooa and N-propylolarDamolloo, As / l-CClalkalOlloamlo group flrmlmidldoo8 and propylatealkyl group Yl, Methyl, 2-ethyl or 1-, 2- or 3-polypropyl, substituted with (14c; 11k3xyl) group (like methoxy or ethoxyl), cyano, carboxylic or (1-Ccalkoxy27) thalonyl (like methoxylcarbonyl) JtlkJykarDlnyllwa / ·

W ^{hen R4} is ^{F and the} iz.jorógiczne acceptable residuals of the alcohol, it is raozta ^k Tor set up suitable ester biodegradability and is selected, for example. Lβ8tępsJęcych the group consisting / l6CC / akkllowa ewamuelnu substituted hydroxy group and / or l4CClaklok ^ ylooę such Like methyl, ethyl, 2-hydroxyethyl, 2-aetolsyethyl, propyl or 3-hydroxypropyl, phenyl and benzyl groups, the latter two being substituted with 1 or 2 substituents selected from halogen (such as fluorine, chlorine, bromine or iodine) groups /^.^/οΙ^^κυ^ / aakich, such as a methyl or ethyl group / and alkyl groups, such as a group ^^ toxyl ^ o ^ wa or Jtolsylloa /.

When R is a / 1-4Clθlknlosulllaamldooa group, it is e.g.

When it denotes a (cc) alkyl group, it is, for example, a mθJylene group, ethylene group, mJylJlow group, ethylene group, 1,1-dimethyl tyJnlowα and 1,1-dima the ethylene group and the other ethylene group being preferred, and especially the ethylene group being preferred.

When A is a (16C) alkylene group, it is e.g. a (1-cc) allyloyl group. As mθJylJlooa, ethylene, tnme t yJenooa, isopropyliJnnooe, and 1,1-dimatylutylernwa / and 3,3-pji2 tilldan. When A is a (2-6C) alkanylene group, it is preferably e.g. a vinylate group,

1,3-plopenyJlnooa and 1,4dCuten-2-yJnnowa that when A represents a lksy / ll6C / alklelnowę, it is preferred, for example. TylJnlwa oxime group, ⁿ oksytet rametyJl OOA / ie. group with ^^ t ^ rze -O ./CH^j/^-/, 1-okoy-l-methylθtyl / i.e. a group of the formula -OC (CH) "- (1 2-oxy-1,1-dimethylethyl) i.e. a group of formula -O.CH ^ .C ^ Ci ^ HH / ug /, it being understood that the oxy ^zg be bonded ^UPE r r \ instead of rings ^ m ^1, 3-d oksmu.

When A contains fluoro substituents, it is, for example, a difborcuethylane group or a 2,2,2-tnfluo-1-oklo ^- 1-trifluoromatylethyl group (this is a group of the formula -OC / CF ^^ - / »

When ^r 3 is a thianyo or furyl group, this is e.g. 2-thienyl, 3-thian6

163 045

Iowa or 2-furyl, optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, nitro, cyano, chlorine and bromine.

2

Q is preferably benzene, and Q typically is a benzene, pyridine or naphthalene moiety, optionally substituted as defined above.

When A stands for the group / WCC / akki lnoii, it is e.g. the group / l-4C / akl / such as misleading, ethylene, trimethylene, isopropyl ^ nia and 1,1-0ιοι ^ 1οι ΙυΙιποοθ / and pentamethylene when it denotes a group (2-6C) acylnene, i.e. it is e.g. vinylene, 1,3-propenylene ii, 4-buJθn-2rylnα, when it is an ocyyl-6C / tilneum group, i.e.

oxymeι ^ / 1ιπ ^^, oxy ^ len ^ a and lxytltramethylnnooa / this is a group of formula • 1 2

1O./CH2/4 ^- / · whereby the oxy trap may be facing Q or Q.

R is generally preferably 1, X is hydrogen, Y is cis-vinylene,

4

A is an ethylene group and R is a hydroxyl group.

2

Examples of R 1 R are the following substituents 1 1 2 a / R 1 R 2, otherwise trffluormmβrylowl b / R ^{! g} roup is ^ę oxygens ^one head ^and Lu ^bf b ^y ^ o ^E, an optionally odstaoion ^p c ^{h a} lofoocem ^g roup ^ę cyja2 new or ritrowę, and R is hydrogen, C R is a ^g roup lrok8y_l- ^{4 F E} C / α ^lk l ¹ o ^e / ^l especially -mθtylo-l- ^{y l} nnoksyet Lowe ^{/, y} parts of ^white spinning phenyl moiety has one substituent such as a group .. / l44C / alkllowa 1 / l 1 CCealloSrylowa eventual with other podetawnik such groan / I44C / βlkyl, / I4CCeallokβylooa, nitro, trifloom back, cyano, halogen, and R is hydrogen, d / R ^{! g} roup is ^ę .ιγ ^ ΙοΙ and / LC / A keels ^{k e} / ^l especially -mθtylo-l-fθnylotlOθtylowę /. the phenyl part is optionally substituted with 1 or 2 substituents independently selected from groups such as (1444C) alkyl, y'l-CCaa, Hok, and Nitfooa, tnf 11lmme, cyano 2 halogen and R is hydrogen, and / ^Ra is ^g roup ^ę nθ ^l you ¹ oo ^e possible podstawiln ^and 1 or 2 basis of this, ^j piece 2 of halogen, / l4CC / θlkllowa luo ntfooa, R is hydrogen and ^f / ^R! is benzyl ^g rupa ^{f y} en Low ^{E, B} θnzylo 8y ^{k l} ln ^{y Lowe} / pyridine ^ u tox ^y / f ^ en ^yl, / ^ us lloθtoksy / lenylowę, fenokBrflrylooę 1 / ^ phenols ey / phenyl.

A particularly preferred group of compounds wytwerzanycn invention comprises compounds of 4 4 ozorze 2, which me R as defined above, A is a / l-4C / ^alkilerloą, X ¹ is iuo ^g roup ^E r ^yy roks ^yl axis. R ⁵ is u ^{p g f} E in the rear ^ę Luo thienyl ^E, an optionally podθtawlon ^{eg EP} ru ^Use anooą c, r and t ^ o ^ ^e / t ^{C l} .4; ^ £ l ^k kl ^{o "E l} ub halogen, or R ^b is a group of formula R ^b .A - in TCT ^ yo R ^b represents a tert ^{yl l e j} ec has JE ^e ^ n pudstawnik, such as a group / i44C / alk1oowa, / l4CCαβiloksylooa, hydroxy, / 2 -fC / alkenylooa, / l44C / alkylt10, / l4C / alkllo8ul0lryl, / l4CC / acryloyloyl, / 2-5C / aleanollowα, carboxylic, / l-cceβllocry77carbonyloa, / N- / l-4C / alkyl / lCarbamoyl, alkanolylne or (144C) alk11a, the last being substituted by (l-cceilloxy, cyano, carboxyl or (i-4C) acyloxy) earbonoyl, and an optional second substituent such as (1444C) alkyla, / 14CC / alloxylooa , trl ^ ₁ llOlMltylowα nitro, cyano or chloroollc ^{means g} roup ^e / ^'l C / ^ 1 ^ LKI now ^é, oxy ^ - ^ C / ^l in alkilnową bezpośn ^b ^ o ^ not zeiie R ^b and their Uroaceu Together they release the salts.

Ex ^ ^p ładaoi odstawπl ^k OO. angle ^about Re may form part of ^{bl b} R R ^E B can ^YC substituents wymeriorl above and ^R &lt; ^dl.

c

An example of the meaning of R may be a phenyl group containing one substituent / 1- ^ 3 -alkyl / especially a methyl or ethyl group /, / 14CCeβlloxy / ^^ including the ut ^ lc ^ ^ ^ o ^ group / or hydroxyl and possibly a second postheonic, such as nitro, i.e. fluonoethyl or halogen (especially fluorine, chlorine or bromine).

Y ^{P y} kładeoi substituent A ⁴ S ^E podstaonrki p-α are higher for \ ^g d ^s Ident ^and connectors on the RU ^{g PE} / 4C {^ y ^^ ^ KK3 1NO ^ Oe rp. ethylene, tromillin 1, 1,1-d and thymol, with the ι ^ Ιθποοι and tromethyl groups being preferred

2

Examples of the substituent A are those given above for A when it is a direct attachment, (WCC) alkyl or oxyyl-4C / alkylene group such as direct bond, isopropylidene yl, 1-dimatyyleatyl, 1-oxy-1-rnatylatyl / this is a group with the formula -OC / CHh / j ^- /

^Getting clade ³ R S ^E na9tę ^p uj ^a Ca ru ^g and ^l-py nohylowa 2 ^{- l} Half ^oil, 2-chl ⁿ r ⁿ -l-naphthyl ^{a TY1} words, tOenylowa-2, 3-tianylowa, 5-cyano -2-oxygen, 5-brn-oi2-thien / lyl, 4-brn-oi2-thianyl, 4-chloro-2-thianyyl, 5-chloro-2-tanyl, 2-furyl, 5-brn-Oo-- furyl, 1 - / - methoxyphanoxy-1 - atylnatyl, 1- / 4-t-buty1phanox // - = - 0 thyInatylnwa, 1 - / - matoxyphenoxy / -1 - atylatin, 1- / 2- --tyyotufanoksy / -l-mat / loethylowa, 1- / 4-natatylot iiOenokey / łl-butterflyatyłowa, 1- / 2 - atylosu1fon / lnfonok8y / -l - rear otyloo, 1- / 4 - at / losll0on / lo0oeok8y / -llmety1oβty1owa,

1-matyl-1- (2-matylphanokey) -atylo, 2-phenylntioaanyl, 2-phenylsulfenylphenyl

2-bifan ^ it-towa, 2-benzol ^l ofβn ^y looa ^{, o} C -dof ^u nolbbnzylt, l ^ et ^ ol - ^ - mato ^ y-2-phii ^- trophinoxy / -ethylooa, l - ethyl- l- / 4 - atylo-2-ηιtrnfanoxy / atylowa, l ^ e tylo-1- / 2-ma t / lo-6nit rophanoxy / a posterior, l - ethyl-1- / 2-cyJ aeo - / - -tt / lof onoxy / at / lowa, l ^ a tylo-lł / 4-clloro-2-cyJ ano tenoxy / ot / lowa, 1-rna tylo-l- / 2-cyJ aeo - / - lαtoksyfonokey / at / lowa, ^^ γΐο-ΐ ^ ί-ο / Jano-5-lθtylnfonoxy / θt / lowa, l- «ia 10-1- / 2 ^^ rofonoxy / atyłowa, l- ^ hhydroka / f anokko / -! - tylootylowa or / 6 / 22--0toks / styryl,

Another group of particularly interesting zwlęzków produced sposobo- invention nbaj 4 X-Uja compounds of formula 3, A is a group który- / l-4C / alklOnnowę, X is hydrogen, b ^u l ^g ^ ru ^EP hydrnks NWA, A ⁸ is ^g ru ^PE olts ^ t and sulfone ^ these ^k af ^b of ^{n / l} yl, each ^ omoilowę l-innkarDneylooę, / l CC / akkilnoowę, ok9y / l-6C / alkllnlowę or direct military prison with ^{q3, q3} Ident ^a cz ^{and a} bonzone ^, pyridine or naphthalene, R ⁷ and ^r8 eιesis ^and ore are hydrogen, cadyl, cyano, ntrach, / -44C / alkyl, / ł / CC / al1oSsy1 or trofoil-ethyl,

R ⁴ -a as defined above, and ar-lc ^{hf y} acaut hand acceptable salt thereof.

Exemplary-i a4 wo ^^ orza 3 are the bases dimensioned above for formula 2.

3

Example-1 A are basins o ^ ι ^ l ^ r ^: Loeo higher for A, such as the / Ł6CC / accolin group or nksy / l-ec / alk lOnno, e.g. -at / lannwβ, ot / lano, isoprnpylanic and ox / rnatylone, As well as ix, tin, sulfonyl, carbonyl, carbo-oyl, l-l-carboeyl, and bosprod3

-a binds to Q.

δ

Example R ⁷ R ^δ or a halogen Se fluorine, chlorine and nro- as an alkyl group -ethyl ot / group, the alkoxy group -etoksylooa 1 otoks / lowa and hydrogen, cyano, and nuiowa trOfloon-netylowa. Q typically is Oee / Io or plridyl:.

3 6

For example, the groups of the formula R ^8. Q ³ " ⁶ - in the formula 3 are phono, Oanylthio, phonylsulfonyl, phenyl, benzoyl, bansyl, benzene, 4łC / Jaeobnzyloxy,

2łpl / ydyn - atoks / looa, 3łplrydylot> ethoksylooa, / -pl / ydy1o-ethokβ / lowa, Oanokeyrnatylowa, 2-naphtyl tylo-atoks / lowa, 2,5 «'dl-αtokβybeezylok8 / looa, 4-eltnzylCooobaae / loks / 1owa 4 14

In particular, R is hydroxy, X is hydrogen, and A is ethylene.

The preparation of the new compounds and their familiarity with the acceptable salts of the present invention is described in the examples, examples 18, XIX, XX, XLVI and XLVIII of which describe methods for the preparation of particularly preferred compounds.

Imposition ^y appreciated żo the compounds of formula ^{1, R4} is ktćiry- ^g roup ^{Eh / d y} roks low ^ę Luo aikanotu0lenβ-ldnoę that a-fotαr / czee and -ogę salt form both acid and with base-i . Preferably, a pharmaceutically acceptable salt of such compounds, both, e.g., solo alkali steels and alkaline salts, a salt with organic a-inan and a quaternary base-ι giving ^^ physiologically acceptable cations, such as a -atilanine salt, dilθt / intmna, tm-ethylcarin, otylenollallea, ρ ^ par / l / n; -olfoline, p ^ i ^ dyne, piperazine, ot anolamine, route nnonoamine, N - ^^ tilngiukarn.ną, with hydroxylate-tatra-atyloa-ohm- and volatile gasoline tyla-rnonium-, as well as solo zk ^^ sa ^^ giving physiologically acceptable anions, such as solo with acid-i -maralny-i, e.g. with acetic acid-i-aaki-i like hydrogen chloride lun brorn ^ nvlor /, with acid-siacl (} wyfl and 0nstolic- iz - strong - and organic acid, e.g. from p-toluene sulphoic acid and -O ^ 51101 ^ 101 / -,

The method according to the invention for the preparation of a sol 2: the -ethyl or ethyl group and the other the -ethyl group; or a gold oxide with the formula R.CHO / or its hydrate, ace6

Of thallium or hemiacetel (in the presence of an acid), such as one of the ones mentioned below, preferably at a temperature in the range, e.g., 10 to 80 ° C, and optionally in the presence of a suitable solvent or diluent (also such as one of those mentioned) below in p. a / <

4 1

The starting compounds are prepared as follows, except that R, R, R, X, Y, A and n as defined above

2 e / Diol derivative of chip 4, in which One of T and T is a hydrogen atom, and the other is a hydrogen atom or an o-group: o -CRa.Rb.OH / in which Ra and Rb are the same or different (I44C) alkyl / t ^o is subjected to reaction with an aldehyde pochio N, ^e with the formula R ^a .CHO or an acetal ^j e ^j, pólacetaeam or ^! ^ zeatemι

An aldehyde (or its hydrate or acetal or hemiacetal with (14H); (aklohol) such. Like m8nol or ethanol / can preferably be ethosized in the tadmler.

The reaction is usually performed in the presence of an acid such as hydrogen chloride, hydrogen bromide, sulfuric, phosphoric, methanesulfonic or p-toluanosulfonic acid, preferably in the presence of a suitable solvent or diluent such as dichloromethane, toluene, xylan or an ether, e.g. tetrahydrofuran, dibutyl ether. , methyl tert-butyl ether or 1, Z-dimethokeyethane and at a temperature in the range, e.g., 0 to 80 ° C.

2 d) The starting compounds of formula IV, in which T and T represent a hydrogen atom, can be prepared e.g. by mild, acid-alpha-alkoxylated hydrolysis or alcoholysis of the dioxane ring in a compound of formula V in which one of Ra and Rb represents a hydrogen atom or a group / ^ CJ / akkyl / aake Like methyl or ethyl / and the second is a group (1444C / βlk11), prepared by a method analogous to that described below in d), e.g. analogous to that described in European Patent Application No. 94239. Hydrolysis or alcoholysis typically carried out at a temperature in the range 10 to 80 ° C, using an aqueous solution of a mineral acid such as. Like hydrochloric acid, in an alcohol such as ethanol or 2-propanol, or in an ether such as tetrahydrofuran as solvent.

2

The starting compounds of formula IV in which one of T and T is hydrogen and the other is a group of formula -CRa. Rb.OH are intermediates in the above-described reaction to prepare starting compounds of formula IV, in which both T and T I mean hydrogen atoms. However, these intermediates are usually not herbal and not characterized.

In some cases, it is necessary to process zmoOyflklwanle / a / and / b /, if an aldehyde of formula R ^{a CHO,} łctćiry bristles is not rea tive ^k i.ub tend ^E to form ^{the N-} and a acyclic hemiacetal when reacted with the compound of formula 4 or 5, for example. when the preparation of compounds of formula ^k in ^ra is tórym ^g roup ^{c e} ^ ers uoroatylowę are used t ^o ^ penta uonpnpionaldehyd. Thus, the method according to the invention also includes the procedure,

2 c / Which consists in the reaction of a compound of formula 4, in which one of T and T represents a hydrogen atom and the other is an alkenesullonyl group (especially methanol) or arenlsullonyl (especially berisene - or toluenesulfonyl) with an aldehyde. in the presence of an acid as a catalyst and in the same general conditions as described above for the process (a), then on the catalyzed base cyclization of the acyclic intermediate, e.g. with an alkali carbonate or hydride, ^ nego such as potassium carbonate or eodu hydride, in a suitable solvent or diluent / aakni I ^{k y} opisen piowyżej ether / at a temperature in a jogging suit, eg. ^{2 O-5} ° C.

The necessary starting elkanosillonyl esters or arenesulfonyl esters of formula 4 are defined as

2 above can be conveniently prepared from a suitable day at 4 (T = T = hydrogen) by reaction with one molar equivalent of 1 of a suitable elkyl or αrenosilphonyl halide such as lithium siphonyl chloride or p-toluenesulfonyl chloride in a suitable solvent or diluent aakn. Like ether or dichloromethane (at or around ambient temperature and in the presence of a second base (such as triethylamine or pyridine) for the preparation of compounds of formula I where Y is olnylnoyl and R is hydroxy, aldehyde of formula 6 ^ p ^ s ^ it is reacted with a Wittig odczytnikeθm formula R jPnCH.A ^a .oo ^o_ M * ^k t ^O wherein R is a group / l66C / l aalki ^ »erylow E or ^E / especially

M + is a cation, e.g. an alkali metal cation such as lithium, sodium or potassium.

In this way, the desired compounds of formula I are produced, in which the sub-equilaterals with the double bond are mainly in the preferred cis position, i.e. in the form of the Z isomer. However, small amounts of analogous compounds with relative trans / i.e. E) isomer, which can be removed by a conventional method such as chromatography or crystallization.

The process is preferably carried out in a suitable solvent or diluent, e.g., an aromatic solvent such as benzene, toluene or chioetoanzane, an ether such as 1,2-damettxytane, t-butyl methyl ether, dibutyl ether or tetro-ether. ^ n, in dimethyl sulfoxide or tetramethylene sulfoxide, also be in a mixture of one or more such solvents or diluents. EIE process is usually carried at a temperature in the range, for example. -80 ° C to 40 ° C, but preferably in the tem ^ er ^ turca or near room, for example. Cornering ^August O ° C to 35 ° C.

For the preparation of compounds of formula I where x is hydroxy, the compounds of formula VII where P is a protected hydroxy group including the (-44C (actoxyl) group) are removed by conventional method.

Examples of particularly protected hydroxyl groups include, for example, groups (-4CC / alo ^ ^ Ne), such as rmeoxy, bnzyloltyl, alltlSyt, tetranydropyran-2-yloxy, / -4C: / al / zo ^ 3u ^^^ ny ^ oxss (especially meeanosslfonyloxy) and trialkylsliilkxes containing up to 10 carbon atoms.

The conditions for the removal of the group c / wandering depends on the type of this group. Methods for the removal of particular protecting groups. Except for the hydroxyl group, they are well described in basic textbooks on organic chemistry, and such conventional methods, well known in the art, are employed in the process of the invention. For example, individual groups remove 6ia as follows; / 1 / allyl or t ^ et rahydropiran -yoowę - by the action of an acid sUnym ^{tall, j} k vibrant floo tooctoo ^are in tei ^^ e ^ ees for example. ¹⁰ to ⁴ 0 ° C / 2 / tr lalkiJs llilwwę / eakę ^j a ^k t-butyldimethyls 1111 ^ 6, which is preferable - by reaction with aqueous rocotr ^ ^ M tettDbuSylommontovegt fluoride or sodium fluoride, conveniently in a suitable solvent or diluent such as tetrahydrofuran or t-butytomyltytite ether and usually at a temperature hereof «En in or similar ^, e.g. in forest ¹⁰ to ³⁵ ° ^ / 3 / alkanosHonyJwę ^- by tnydrolysis in the presence of a base / such as sodium or potassium oxide / in a suitable aqueous solvent / longline ^{, j} a ^k ^^ ^d n ^ ^y sol / JCC / aJoholu / and mmoeraturze eg. ^{0 d 60} ° C / ^4/1 l αl .ow ^{t e} - by the action of ttoakthhotnaem meealu αlkalJcznθgo or difθnylofosforka-m / such as sodium tioatanolan solvent is ¹ l - ^{, j} a ^k t ^ -dimic ^ nne ^m id in e.g. 5 ^0-1 6 ⁰ ° ^C f, lithium diIzylphosphide in a solvent such as ether ma) ^^ OHOo ^. Dutite (^ y or tati ^^ hy drofuran at e.g. 0-60 ° C or / 5 / benzyl - through the cat / lcoowase / palladium hydrogenooysis in an alcohol such as ethanol at or near ambient temperature or by using an alkaline medium such as sodium in clθkSym / -ο ^ θ ^.

The present invention also includes a process f / ^and nalo ^g ic ^E to the e /, in Icjrej a ^h y ^d oo ^k s ^s Lowe ^ Egan as pod6tawni ^k <JLA ^R is introduced by removal of a convenient group ochronnee group such as / Jcc / e lk tallow, especially tmeyl. Removal is carried out as a last step, e.g. using the conditions described above for the hydroxy-pyridyl group.

gg / an ester of the formula is decomposed, in which R is the group (l-CC / ecclt / especially methyl, ethyl, propyl, or t-butyl), phenyl or benzyl, the latter two may be optionally substituted with 1 or 2 βΙομ -ι halogens, with / l4C: / akkllic or / ^ cC / al ^ ss ^ oic groups ..

The decomposition can be carried out using one or more conventional reagents and under conditions which are well technically suitable for the conversion of esters to acids. Thus, for example, it is advantageous to decompose a washing process. Hydrolysis, for example, by using an alkali metal hydroxide such as lithium, potassium or sodium hydroxide in an aqueous medium, preferably in the presence of a suitable solvent or diluent or

Such as tetrahydrofuran, Methylmethyl ether 1 at a temperature in the range, e.g., 10 to 60 ° C and preferably at or near ambient temperature, For butyl, thermal decomposition can be carried out by heating a compound of formula 6 at a temperature in the range, for example, of b0 to 15 ^° C, alone or in the presence of a suitable diluent such. Like diphenylether or diphenylsulfone.

n) for the preparation of compounds of formula I in which Y is ethylene, the compound of formula 9 in which Y is phenylene or an atinylate is hydrogenated.

Uwoldlrlnlt is preferably carried out in the presence of a suitable catalyst such as a noble metal catalyst, e.g. palladium or platinum, suitably on an inert support such as carbon ¹ , barium sulfate, barium carbonate or carbonate, using hydrogen underneath it. -2. 10 Pa, process of ^ disable carried ^SIU in a ^ im ^ fresh rozpuszczalmku or diluent, e.g.,. / 1 CC / akkarnlu / κ like ηο ^ !, propand ethanol or / and at a temperature in the range, for example. 15-35 ° C.

The process according to the invention also comprises moodffering the above procedure, suitable for the preparation of compounds of formula I in which Y is an olnylenyl group consisting of

A partial bleach of a compound of Formula S, wherein Y is ethynylate. In this molification a suitable poisoned catalyst is used, e.g. a Lindlar catalyst such as palladium on calcium carbonate, poisoned with lead, together with similar solvents and at a similar temperature as in the process h), and) For the preparation of the compound of formula 1, wherein Y is methylene chloride, the alcohol of formula 10 is reacted with an alpha-amic acid derivative of formula 11 in which L is a leaving group, e.g. a halogen such as chlorine, bromine or iodine, an alkanesulfonyloxy group such as a krenoβulflnyloxyoxy group such as benzene or toluene sulfonyloxy.

The reaction is preferably performed in the presence of a base such as an alkali metal alkoxide such as sodium methanolate or sodium ethylene, a hydride such as sodium hydride or an alkane derivative such as butyl lithium and in a solvent or diluent suitable for such base, e.g. in / 1-CC / ackanol when an alkali metal alkoxide is used, in N, N-dimethylformamide or ether, such as tetranydrofuran or t-butyl methyl ether, and ether when meslalkane hydride is used and in ether when an alkane derivative is used . Generally, the reaction ^ę ne (^^ βάζΐ ^SIU at a temperature in the range-e ^{0 0} ~ 5 ° C. ^The fresh-lu irzyia al ^{dk y} is preferably, when forming the EOL alkholu of formula 10 by reaction with a suitable base, and then the resulting salt is reacted with the ammonium acid derivative of formula II in a suitable solvent or diluent, such as oymnlone above. Note that when X is hydroxy, it is usually necessary to protect this substituent from c ^ ^ and ^ and ^^^ for a hydroxyl group with a protecting group such as dimenlltt in process e) above, prior to the initiation of the process and /, followed by removal of the protecting groups using conditions analogous to those given in process e).

The necessary starting materials for the above methods (a) - / and / can be prepared by well-known methods for preparing structurally similar compounds, e.g. by methods analogous to those described in European Patent Application No. 9-23931 and European Patent Application No. 98690A2.

Aldehydes of formula 8 can be prepared, for example, as shown in schemes 1 and 2 in the examples. Alternatively, a specific enantiomer may be prepared starting from the specific tnanlJorar 3-2- (1-phydloxy-1-plriphylmmethyl / peyt-4aynyl) oxazollfyn-2oon of the formula 14, wherein R is (1-4C) alkylne / ^ ^ o ^ aszlza. isopropyl / obtained from condensacc and aldo ^^ ldpowoedyίtgo 3 - / ^^ 1- (1 (^ tenoyl / oxazolidine ^ -one with pyridylcarbonylhyde, as shown in Scheme 3.

A protected hydroxyl derivative of formula 7 can be prepared, for example, by carrying out the above process / a / or / b / with a suitable 1,3-dane analog compound of formula 5, but wherein X is a suitably protected hydroxyl group, such compound is readily prepared by standard methods analogous to those described above and exemplified in the examples.

163 045

Corresponding diols of formula IV, used to prepare diocanes of formula I or 5 in which the pyridine group is substituted with X and the alkanoic acid side chain has the cis configuration, can be prepared, for example, by a method analogous to that described in European Patent Application No. 142323, starting from from the appropriate pyridine carboxaldahide and succinic anhydride and the corresponding base as used in reaction (ii) in Scheme 3 for the aldol condensation.

The esters of formula 8 can be prepared, for example, by the method (a) using the corresponding diol ester corresponding to the burrow 4.

Compounds of value 9, in which Y is an ethynylate group, can be prepared, e.g., as shown in Scheme 4. Alcohols of formula 10 can be obtained from of formula 10, in which n "2" by conventional hydroboration (borane) followed by treatment with hydrogen peroxide / or by reduction of the corresponding aldehydes / e.g. sodium borohydride / o 6, e.g. as indicated in Scheme 2 to give compounds of formula 10 where n-1,

12

Aldehydes or ketones of the formula R.CHO or R.CO.R. which are novel compounds can be prepared by well known methods such as described in the examples below.

The required Wittig reagents can be prepared by conventional methods, e.g., by reacting the appropriate phosphono halide with a strong base. As sodium hydride, lithium diisopropylamide, potassium t-butoxide or butyZotlt. Usually, it is produced in situ prior to condensation / d /.

It should be understood * that the compounds of formula I in which R is ydrocayloin may also be prepared by other methods known in the art, e.g. by catalyzed base hydrolysis of the corresponding amides or nitriles. Also, this concise! of formula I, in which R is not hydroxy, can be prepared by mono-esterification or sultonamming from compounds in which R is a hydroxyl group and / or a reactive derivative thereof / and the corresponding alkono, phenol or / l-CC / alkynoβuitonemide. Such methods also fall within the scope of the invention.

A salt of a compound of Formula I is prepared by reaction with a suitable base or acid providing physiologically acceptable ions or other conventional salt formation method.

In the case of the optically active form of flour of formula I, it can be prepared by any of the above methods using an optically active starting compound / e.g. the method described in examples XLVI and XLVII /.

Alternatively, the racemicrin form of the compound of formula I can be cleaved, e.g. by reaction with an optically active form of an appropriate organic acid or base, e.g. followed by conventionally ionic separation of the diastormoric mixture of eoles, e.g. by phacctonic crystallization from a suitable solvent, e.g. (-4CO) / alcohol, whereupon the optically active compound of formula I can be liberated by treatment with an acid / base / by a conventional method, e.g., an aqueous mineral acid solution such as dilute hydrochloric acid (or an aqueous alkali solution such as an aqueous sodium hydroxide solution).

Wale zpis / yyzh in this description of intermediates sten new compounds, e.g. flour of the formulas 5 / Ρ / οΡΙ3-θΙυΖ /, 6, 7, 8, 9 and U.

The following reagents are used in the reactions shown in Schemes 1, 2, 3 and 4: Scheme 1:

/ 1 / NaOEt / EtCH / allyl bromide / ii / LiAlH. or LiBH./THF

I o * 1 o / Ui / TsOH ^, R ^a R.00 l. Or R ¹ R ² .C / OM ^ ^j ' ² / W Zn / BH ^, Et2O / ^v / 03, CHgCirg · next Ph ^ P, or OsO ₄ , NaJO ₄ , N -6uOH, RNO, V, NaH, CMSO. ęrCH2ωH ^ 0Mί ^ z'2

163 045 / νιι / Η *, η ₂ 0

R ο (14,4C) alkyl such as methyl (Me / or ethyl / Et),

Ts a p-toluenesulfonyl Scheme 2:

/ 1 / ^B 2 ^H 6 'eetępme HgOg /ii./ chlorocnromien pyridine, CH2Cl2 or OCD, 0M> 0, pyridine, TFA / Ni / NaBH4, EtOH / iv / Tacl, pyridine "seq ^p is not ^N aO / acetone 40 -60 ° ^C / v / ^{1, 3-ditlan,} LiN / i-Pr / ² THF at 78 ° C / VI / / N ^H _4/2 ^C e / NO.j / ^g - cerium nitrate ^amonlowo-y / IV /, ⁰ ° C Scheme 3:

/ i / penthenol chloride BuLi / THF / -78 ° C / ii / Bu2B.S02CF3 // i-Pr / 2NEt / pyryyincarbokealdehyde / CH2Cl2J HgO4 / pH 7 / in / NaOR / ROH ^ "ra / 1- ^ C / elkyl such as meey ^ / / iv / LiAiH.TTHF 1 2 * / v / R. R .00 / p-toUuenesulfonic acid / p-TsOH '/ vi / Oy / CIHCl3, then Me ₂ S or Ph ^ P.

Scheme 4:

/ 1 / ^, EtOH, Br / CH_ / .C "CA ¹ .00 ² R / 11 / NaBH ^ then R ^I R ^Z ^^ ^, Ts ^O H / 11i / NaOR / ROH / iu / LlAlH.THHF 12 * / v / RR .00 / kwa6 p-toUuenesulfinic / p-Ts.OH/ / vi / O ₃ / CH ₂ Cl ₂ , followed by Me2S or Ph ^ PR a / I44C / aikyl, such as Me

As previously stated, compounds of formula I have significant TXA ₂ antagonist properties and are inhibitors of TXA2 synthesis. Antagonism against TXA2 can be demonstrated by one of the following standard tests:

a) Model based on rat aorta strips analogous to the model designed by Piper and Vene (Nature, 1969, 223, 29-35), in which the TXA2 mimetic known as U46619 (described by R.L. □ onesa et al. in Cnemutry, Biocnem ^ try and Pnannmaooogical Activity of Prostanoids * ed. S.M. Rooerts and F. ^ cheinmann. p.

211 »Pargamon Press, 1979 / jb / Platelet aggregation test based on the test described by Borna / Nature, 1962, 194, 927-929 / and foreigner:

/ 1 / aggregation of human plasma platelet-rich., Cytrynowanaj by the addition of the TXA ₂ mimetic agent U46619, and the resulting dose-response curve odpowwedżi / ii / obtained dose-response curve for agregacci by U46619 stimulated platelet in the presence of increasing ^j ącyc ^h .Iości ^b and ^d ane ^g of compound / zw ^ le in zalesie 1 ° ^b M ^d of 1Ο ~ ^ θΜ / 'and / 111 / calculating values Kg indicating the effectiveness of the antagonist activity against TXA _2, the test compound, which is the average of several concentrations, from the calculated 50% of the response value to aggregation with U46619 in the presence and absence of test compound or c / bronchoconstriction test including measurement of ham ^ f ^ oΓ ^ iα by test compound bronchoconstriction induced by the Konzee t-Rosslers model of anesthetized / modified Muscovy by Collier and Janas, Brnt.J. Pharllαcr ,. 1967, 30, 263-307 / by intravenous administration of TCA ₂ mimetic - U46619 and including:

/ 1 / obtaining a kumlUuU ^ increasing dose-response curve for bronchoconstriction induced by U46619, which is administered intravenously as constant volumes of a solution in physiological saline with increasing concentrations of U46619 / 0.2-4, / ug / kg /, and stenosis the bronchus is expressed as the maximum of the theoretically moolese ^^^ enzyme to be obtained without regurgitation to the reefed animal.

163 045/11 / obtaining a cumulative dose-response curve for bronchoconstriction induced by U46619 at 30 minutes intervals over a period of 3 hours, after oral dosing of the test compound and / 111 / calculation of the dose ratio of U46619 for the test compound / to Jeet of the concentration ratio U46619, which cause 50% of the bronchus in the presence of 1 in the absence of the tested compound / vacant antagonistic power against ΤΧΑ ₂

The test / b / can be advantageously arranged to perform an antagonism to TXA splitting. in vivo by assessing the effect of the test compound on platelet aggregation after administration of the compound to a laboratory animal such as a rabbit, rat, guinea pig or dog. However, when a dog's platelet aggregation is tested, it is necessary to use an aggregate agent with ΤΧΑ- U46619 platelets, adenosine diphosphate, at a predetermined threshold concentration (about 0.4-1.2 x 10 M).

Antagonism against the effects of TXA ₂ on the vascular system can also be demonstrated, e.g. in rats, by the following experiment:

d / Male rats / ^^^^ ep Aidarley Park / are anesthetized with sodium pθntobaΓbltβaθm and blood pressure is monitored at the carotid artery. The mimic TXA ₂ U46619 is administered intravenously at 5 µg / kg through the jugular vein to produce an increase in systolic blood pressure of 2640-3970 Pa. This process is repeated two times in order to ensure the correct insertion. The test compound is then introduced either intravenously / via the jugular vein / or orally / via a cannula / directly into the stomach 1, the animal is administered with a U46619 loop minutes after dosing of the test compound 1 then successively every ten minutes until the hypertensive effect of U46619 ceases to be blocked.

The property of the test compound for inhibition of TXA2 synthase can be demonstrated in accordance with the standard in vitro test / test / e / _ / described by Howwrth et al. / Blochem. Soc. Transactions,

1982, 10, 239-240 /, in which the microsomal preparation of TXA2 synthesis from human plates is used 1, the quantitative cloncovine radiochromatograph is used to evaluate the convlaβJi _- 14 "acid / 1- C _ / - atccnytooowago to the TXB2 thrombocaine, which is a meeabolieem B2 ₂

The property of the compound ham ^ ^ ^ lt ^ iβ of the TXA2 synthase activity can also be demonstrated by the method of obtaining blood samples from laboratory animals / usually rats, but also Md ^ guinea pigs ^ klch _l rabbits or dogs / receiving test zwl.ęzek, usually orally. Comp potrakocwane means przeciwkrzapllwyui first ^^ in it at ³⁷ ° C with Itolagenem / ^Getting otuta ¹⁰⁰ yjM /, follows ^{EP 0} aie not uIjsz of intii toeam c ^ ^yk LDD ^k y ^{y g} enaz In matacynę ^ / ^s Ex ¹ 0 ~ ^ M /, rotating ^AIU and dznacz ^and the ^ ziom mβtabbditl TXA2 "TXB2 using standard techniques radidluuuuododrczneJ. By comparing the amount of TXB2 in the plasma of animals dosed to the test with the amount of TXB2 in the plasma of placebo-treated animals, the inhibitory effects / activity of ΤΧΑ synthase activity can be assessed.

fc 1 4

In general, the compounds of formula I, in which R ^x 1 R 2 carries a hydroxyl group, shows activity in the following ranges in one or less of the above tests: test / a / s pA ₂ > 5.5 test / b / s Κθ <1 , 5 x 10 ^-6 M test / c /: dose ratio> 5, 1 hour after administration of 10 mg / kg test / d /: significant inhibition of U46619-induced hypertension during at least 1 hour after oral administration of a dose of 50 mg / kg or less test / e / ^: <1.0 x U ° “ ⁶ M test / f / s significant hav ^ t ^ lt ^ la of TXB _{2 production} 1 hour after dosing 100 mg / kg or less.

There is no apparent toxicity or other adverse effects when using the formulas of formula I, which showed activity in in vivo / c /, / d / or / f /, at several times the minimum effective dose.

The compounds of formula 1 wherein R is other than Me group ny ^ - ^^ _J oxyl usually wykozuję mntβJsza activity in the above tests in vitro, but podoonę activity to okty / ndści to fresh beef ^wheel formula 1, ^R4 is Iktórym ^g ru ^EP hydro ^ ^^ head in testacn ln vivo.

163 045

By way of illustration, the compound of Example 1 has both antagon- antagonistic properties and properties for inhibition of the synthesis of ΤΧΑ? as indicated Kg of 3.0 x 10 M in the assay / 0 / i = ^4,0 x O ~ ¹ ° ^M in the ^COG c ^and e / a /.

As previously stated, due to the combined properties of TXA1 antagonists and T1A4 synthase inhibitors, the compounds of formula I can be used to treat or prevent choro-morbidity or unfavorable conditions in warm-blooded animals related to TXAj / Uub with prostaglandins h ₂ , 0 ₂ and /! ud F ₂ alpha /.

In general, the compounds of formula I are administered for this purpose orally, rectally, intravenously, subcutaneously, intramuscularly or by inhalation, so as to administer a dose of, for example, 0.01-15 mg / kg body weight, up to four times a day, depending on the method. the administration, the course of the disease, and the size and age of the patient.

The compounds of formula I are generally used in the form of pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof, as defined above, together with an acceptable diluent or carrier. These compositions may take various dosage forms. For example, they may be in the form of tablets, capsules, solutions or suspensions for oral administration) the form of suppositories for rectal administration) the form of sterile solutions or suspensions for intravenous or intramuscular administration) the form of an aerosol or a solution or suspension in a nebulizer for inhalation and in the form of a powder, together with a pharmaceutically acceptable liquid compound. Like lactose, for administration by wdmuuhiwaalθ.

pharmaceutical compositions can be prepared by conventional methods using pharmaceutically acceptable diluents and carriers well in the art. Tablets and capsules for oral administration may advantageously be prepared with a enteric-dissolving coating, e.g. containing cellulose tenophalate, in order to minimize contact of the active ingredient of formula I with gastric acids.

the pharmaceutical compositions may also contain one or more sub-substances known to have an effect on the diseases or conditions they intend to treat), e.g., pharmaceutical preparations containing the compounds according to the invention, intended for the treatment of cardiac diseases or ethans they may also contain a known gooseberry and platelet inhibitor, a blood lipid lowering agent, an antihypertensive agent, a clotting agent, an anti-inflammatory blocking agent, or a dilating agent. dishes. Likewise, pharmaceutical compositions containing the compounds according to the invention for the treatment of pulmonary diseases or conditions may advantageously contain, for example, enzyme, steroids (such as bacon dipropionate, sodium πιοglycate, phosphodiesterase inhibitor or Detnant). ndralerglczly means of extraction / ianżly.

In addition, a known TXA ₂ antagonist, such as a preferred compound described in European Patent Application No. 201354 or a known TXA ₂ synthesis inhibitor such as daz ^ ^ en or dazepol, may be present in the pharmaceutical in addition to a compound of formula 1 or a pharmaceutically acceptable salt thereof. furegra (lat / U63557J) to modulate the overall balance of TXA2 antagonizing and TXA2 synthase inhibitory activity to achieve the desired therapeutic effect in any of the above-mentioned disease or condition.

In addition to the above-mentioned use in rneeycynie taΓnpautycznej, compounds of formula 1 are also cenymi ilmmlclczyml pharmacological agents used for development and ^one staldaryzacji tislowżch systems for the evaluation of the effects of TXA2 in laboratory animals such. Like cats, dogs, rabbits, snaps, rats and mice, contributing to the ^^ m quest for new and improved therapeutic agents. The compounds of the formula I can also be used due to their ability to contain TXA2 and inhibit TXA2 synthase to help maintain the viability of blood and blood vessels in bloody animals (or parts thereof) in which artificial circulation outside the body, e.g. limbs, occurs. or bodies. The compounds of formula I, or the physiologically acceptable salts thereof as used herein, are generally administered in this manner to obtain a constant concentration in the range, for example, 0.1-10 mg / l in blood.

The invention is illustrated by the following non-limiting examples. In Example 14, the preparation of the starting compound of formula 5 is described

All examples, unless otherwise stated, / 1 / concentration and evaporation were carried out in a rotary evaporator under reduced pressure, / and / the operation was carried out at room temperature, i.e. in the range 18-26 ° C, / in / flash column chromatography was carried out on Fluks Kieselgel 60 / catalog no. 670738 / from Fluka AG, Bucha, Szwajona CH-9470, / iv / yields are given for illustrative purposes only and they represent the yields of max. milk possible to obtain, / v / spectrum NMR was typically determined at 90 or 200 MHz in CDCl 2 using tetrematylsilane as the internal standard (TMS) and expressed as random shifts (delta values) in parts per million with respect to T 2, using conventional abbreviations for determining the major peaks: s - singlet, m - muutiplet, t - triplat, br - broad, d - doublet, / vi / all end products were isolated as racemates and all showed satisfactory microanalysis *

EXAMPLE 1 0.325 g of p-toUnosilane / awθgo acid is added to a solution of 0.469 g of kwaeu 4 (Z) -6-52,2-dimθnyl-4- (P-trinidol -) - 1,3 dioc8an - i-n5-yl in 7 ml of acatonitrile and the mixture is stirred for 0.5 hour. Then a solution of 0.894 g of 2- (4-methylethoxynf.nooxn / -2-methylpropylpanthyl) in 5 ml of acetonitrile is added and the mixture is heated to reflux for 18 hours under argon atmosphere and the mixture is allowed to cool. The solution is eluted with 2M aqueous sodium hydroxide solution and partitioned between water and ethyl acetate. The aqueous phase is acidified with acetic acid and extracted three times with ethyl acetate. The combined organic extracts are dried over MgSO, and concentrated by evaporation. An oil was obtained, which was purified by flash column chromatography, first eluting with dichloromethane and then with methanol and then dichloromethane (1: 10 v / v). ^ romuja eii 0.345 g of acid 4 / Z / -6- £ / 2,4,5th / 2 - / l- / m-methOxifanxZ-1-romeyJotyio / - 4/3-pyridyl / - !, 3 -dokea-5-yl-nakeane as an oil which solidifies on standing: NIMRt 1.35 (3H, s), 1.38 (3H, s), 1.55-1.8 (2H, m), 2. 25-2.55 (5H, m /, 3.75 (3H, s), 3.95-4.25 (2H, m /, 4.75 (1H, s), 5.1-5.5) (3H, m), 6.75-7.0 (4H, m), 7.35-7.75 (2H, m) and 8.5-8.6 (2H, m).

The output constituent / A / is prepared by the following ep / s / bem:

(1) of a solution of 2.3 g of metallic sodium in 200 ml of methanol, 17.9 g of 2-^^^ ynooyl (methyl acetate) prepared by the method of E. Wannart 1 mn, O.Org.Cham., 1983, 48 The 5006/1 mixture is stirred at 25 ° C for 30 minutes. Then 12.0 g of allyl bromide are added and it is continued to stir overnight. About 2 g of allllic bromide is added, the mixture is stirred for 48 hours and then concentrated. The remaining oil is partitioned between water 1 atm and the aqueous layer is extracted three times with ether. The combined extracts were washed with saturated brine, dried over MgSO 4 and concentrated. The residue is purified by rapid chrommto eluting the mixture of petroleum ether (60-80 ° C) / 1 acetate / 1: 1 v / v / v / v. 13J ^can be achieved if ^{2 g} / e and ^{k n} ot ęoίl / - ⁴ ° C pantayαnu methyl / B / as blαdożółtθg / oil) NMR 2.6-2.9 / 2H, m /, 3.7 / 3H, s /, 4.4 [mu] H, m /,

4.9-5.2 (2H, m /, 5.5-6.0 (1H, m), 7.2-7.5 (1H, m /, 8.1-8.3) 1H, m / , 6.7-8.8 (1H, m / 1, 9.1-9.2) 1H. m /.

A solution of 8.8 g of B in 40 ml of dry tetrahydrofuran is added (11) of a suspension of 1.8 g of illavoglj hydride in 80 ml of dry tetrahydrofuran under argon 1 at such a rate that the temperature does not change over to 80 ° C. FO 2-djinns mixed ozjbia ^SIU in elsewhere. 20 ml of atyl acetate are added to destroy excess reagents, followed by the addition of 50 ml of saturated aqueous ammonium chloride solution. The precipitate formed is filtered off and washed with ethyl acetate. The aqueous phase is distilled off and extracted with ethyl acetate (3 x 50 ml). The combined organic fractions are washed with <RTI ID = 0.0> nten / lt </RTI> brine, dried over MgSO 4 and concentrated. The residue was purified by rapid purification, eluting with a mixture of ethyl acetate and methyl acetate (95: 5 vol / vol / vol). This gives 5.3 g of 2-allyl-1- (3-pyridyl-1,3-pmpandiol / C as an oil / mixture of diastere / 1 isomer: NMR: 1.8-2.2 / 3H, m /, 3.6 -4.1 / 4H, m /,

4.7-5.2 (3H, m), 5.6-5.9 (J, m), 7.2-7.4 (1H, m), 7.65-7.8 (1H, m (J) 8.4-8.6 (2H, m).

/ ni / A mixture of 5.2 g C, 5.2 g of p-toJθnosilę / ower / 1 acid, 50 ml of 2, 2-dimethyloxypropane is stirred overnight in the ty ^ eι ^ ίιtιrza room. The pH is adjusted to 8-10 by addition of tnJ tny / αmmint and the solution is concentrated under reduced pressure. The residue is purified by rapid ahrommtolrttii OoJmπowaJ, eluting the mixture of nail ather / 0 tempe16

Boiling point 163 045 40 ⁶⁰ ° C / ethyl acetate / 6 ° i4 ⁰ obj./obj·/. There are obtained ^4.6 g of 5-allyl-2,2-dimatyl-4- (3-pyridyl) -1,3-dioxane (0) in the form of mesanic 4,5-cio and trans isomers) as an oil: NMR: 1 , 4-1.6 / 6H, m /, 1.6-2.5 / 3H, m /, 3.65-4.25 / 2H, m /, 4.5-5.7 / 4H, m / ,

7.2-7.4 (1H, m), 7.6-7.0 (1H, m) and 0.45-6.65 (2H, m).

(iv) Ozone in oxygen is bubbled through a solution of 3.4 g of 0 in 130 ml of ethyl acetate at -70 ° C, until the solution remains blue in color. Argon is then purged through the solution to remove excess ozone, and a solution of 6.0 g of trieanylphosphine in 50 ml of ethyl acetate is added. The mixture was allowed to warm to room temperature and then stirred overnight. The solution is concentrated and 50 ml of ether are added to precipitate the thiaenylphosilic oxide. Sęczy mixture and the filtrate was concentrated, uzyskujęc oil which was purified by flash column eluting with a mixture of chroπlaSoggaSii / 60 'et 40 obj./obj./ ethyl acetate ^and ether ^y ^ Jo instigation at reflux ⁴ 0- ⁶⁰ ° C / · ^can be achieved if the beginning ^ę tkowo 0.0 g of 2,2-dimβaylo - 4/3-piryddlo / -l, 3-dlo0ssn-cls-5-ylosaeθSalaβhydu / E / as an oil.

NMR? 1.5 (3H, s), 1.55 (3H, s), 2.0-2.3 (1H, m), 2.3-2.5 (1H, b), 2.8-3 . 0 / lH, m /, 3.0 / lH, dd, 0-12HZ, 1.5Hz /, 4.3 / lH, dm, 3 = l2Hz /, 5.25 / lH, d, 0 "3" / , 7.25-7.35 (1H, m), 8.45-8.60 (2H, m / and 9.6 (1H, s), then corresponding 4.5-trans isomer, NMR: 1. 47 (3H, s), 1.57 (3H, s), 2.0-2.6 (3H, m), 3.75-4.05 (2H, m), 4.68 (1H, d, 0 = 1ΟΗζ /, 7.25-7.40 (lH, m /,

7.70-7.80 (1H-m), 8.50-8.65 (2H, m) and 9.5 (1H, brs) in the form of an oil and 0.7 g.

(v) While stirring, an ice-cooled solution of the ylide prepared from 0.91 g of (3-carboxypropyl) trifmylsiphonium bromide and 0.48 g of potassium tartarbusoxide in 30 ml of dry tetrahydrofuran is added to a solution of 0.20 g E in 7 ml of dry tetrahydrofuran (THF) under argon. The mixture was stirred for 2 hours and then mixed with 50 ml of ice-cooled water. The solution was concentrated and an additional 25 ml of water was added, the pH was adjusted to 7, a few crystals of oxalic acid were added and the solution was extracted with ethyl acetate (3 x 40 ml). The aqueous phase is then acidified to pH 4 with oxalic acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with 50 ml of saturated brine, dried over HgSO4 and concentrated by evaporation. The residue was purified on a flash column and eluted with dichloromethane / methanol (95: 5, v / v / v). The yield is 0.19 g of the acid 4 (Z / -6 - / "2,2-dimethyl-4- (3-pyridyl) -1,3-dioason-caβ-5-yl_7hoSseπo ^^ go (A) in the form of an oil : NMR: 1.55 (3H, s (1.57 (3H, s), 1.5-2.6 (7H, m), 3.85 (M) d.

0-12 HZ, 1.5Hz /, 4.15 / lH, dm, 0 ΐ2Ηζ /, 5.15-5.50 / 3H, m /, 7.3-7.4 / lH, m /, 7.7 -7.8 (lH, e).

8.1 (1H, br s) and 8.45-8.60 (2H, o).

2- / 4-mrilato-silo-o-8yl-2-setylpropanal is prepared as follows;) using the following method:

/ vi / To the mτylomsgnase iodide solution / prepared from 32.8 g / 1 ^ DM / magnesium filings and

84.1 ml /1.35M/ iodide maeylu / in 750 ml of anhydrous ether is added with stirring at temper ^and at 0 ° C under an argon atmos ^ sculpted ^yellow soln r 77.18 ^g / 0.54 ^M / mchlorooc methane hydrochloride in ⁵⁰ ml of anhydrous ateru ^of the ^{Barrack p} Towel ^d bone ^ames temperature me ^ pirzeltrocz and 15 ° ^C. Mieszsoin ^ę Mesha ^S and ^E at 25 ° C for you ^g in 30 ^minutes, part of the ^{p y} ^ ia m ozi ^{SIU d} of about 0 ° C. t ^{o s 100} ml nd and Quench the mixture to a pH of 4 is followed using concentrated hydrochloric acid. The layers are separated and the aqueous phase is extracted with ether (3 x 100 ml). The trained extracts are dried over MgSO 4 and concentrated. The residual oil was distilled in vacuo to give a clśnlθnaem 1.lddichloro -hydrl ^k s ^ -2-meth ^{y l} lopropsn in an amount of 5 ^{7, 61 g of p} ostaci ole.ju b.p. ^{48 0} -5 ° ^C after ^d ciέnlθπaem ^{2, 66} Pa · LO ^j NMR: ^1.45 / 6 ^ s ^{/, 2.15} / H, ^b rs / and ^5.65 / IH, s /.

/ vn / To a solution of 21.72 g / 0.175 inda / 4-methylxyphanol in 30 ml of 5.8M aqueous sodium hydroxide solution, 0.255 g (0.7 mmmoa) of cetyltrmesyyl ammonium bromide is added, followed by a solution of 5.01 g (35 mmol) 1,1-dichloro-22-yloxy-22-methyl polyopane in 70 ml of ether. The mixture was stirred under argon for 18 hours, then diluted with 100 ml of ether and extracted with 2M aqueous sodium oxide (4 x 50 ml) to remove the excess phenol. The combined 10O0 extracts are extracted with 100 ml of ether and the organic phase is washed with 50 ml of 2M aqueous sodium hydroxide solution and 100 ml of water. The combined organic extracts are dried over MgSO 4, concentrated and purified via a flash column chrommtoora, eluting with ethyl acetate / hexane / 10% v / v / v and

163,045 yields 3.61 g of 2- (4-methoxyphenoxy) -2-methylpropanal as an oil: NMR 1.36 (6H, s),

3.76 (3H, s), 6.7-6.9 (4H, m) and 9.85 (1H, s).

Note: The above starting materials can also be prepared by a method analogous to that described in European Patent Application, Publication No. 201351, relating to a method for the preparation of 2-phenoxy-2-methylpropenal.

Example II. By a method analogous to that described in example 1, but starting from 2- / 4-Jθrl- ^b utiliphenSsy - 2-mθ-ylpopanal, the acid 4 / Z / -6- ^ 72,4,5-th / -2- / was obtained 1- / "4-tert -butylJ -nooxy-1" methylethyl (-4 - / - polyryyyl) -1.3-diox-5-y-yl) hecaene in the form of an oil that solidifies on standing at 24% yield} NMR: 1.3 / 9H, s /, 1.35 / 3H, s /,

1.4 (3H, »/, 1.55-1.8 / 2H, 2.25-2.55 / 5H, m /, 3.95-4.25 / 2H, m /, 5.1-5 , 5 (3H, m), 6.9-7.75 (6H, m) and 8.5-8.6 (2H, m).

The starting aldehyde is prepared in the form of an oil in an analogous manner to that described in Example 1 from 4-tert -butylJnolyl, 1-dichloro-2-hydroxy-2-methylpplopαsu,> NMRi 1, 6 / 9H, s /, 1.41) 6H, s /, 6.7-7.3 (4H) and 9.85 (1H, s).

Example III. 500 mg of S-cyJanGolophene-2-carboxyaldehyde and 220 mg of p-toluθnosullonoegyl acid are added to the suspension with stirring, 305 mg of 4 / Z / -6 -> / - 2,2-dimθt-ly-4- / 3pplrl-yl acid. / -1,3-dloxac-ci8-5oylh_7heknanow 10go in 10 ml of Jcetonstrile. The mixture is stirred for 18 hours. 20 ml of water and 30 ml of M sodium hydroxide solution are added and the mixture is washed with ethyl acetate (3 x 20 ml). The aqueous phase is acidified with acetic acid to pH 4-5 and extracted with ethyl acetate (3 x 30 ml). The extracts are washed with sodium chloride brine, dried over MgSO 4 and evaporated down. The gummy residue is crystallized from mβ6 ^ lkπ :: s-hexane and ethyl acetate to give 148 mg of the acid 4 (Z) -6- / / 2 »4,5-cis / -2- / 5-cyano-2-thienyl / 4- / 3pplrl-yl / -ll3-dloks-n-5-yh ^ 'hθJsenowθgo as a colorless solid, melting point ¹²⁹ -132 ° C} ^N MR: l, ⁶⁸ / H, m /, I, ⁸⁴ (lH, m / ^, 2 ^ 2 / 4H ^, m / ^, 2.54 (lH, m /,

4.20 (2H, m /, 5.05-5.95 (4H, m), 5.96 (1H, s), 7.17 (1H, d), 7.36 (1H, m /, 7.53) / lH, d /,

7.72 (1H, d / i 6.57 (2H, br s): m / e 383 (M-H).

The 5-cyano-2-methylthloin starting 5-cyano-2-methylthyl is produced by the chromium trioxide / Org. Syntheees, CaJ-lectad Volume II, 441, 1943, / as a colorless solid with an efficiency of 60% and a melting point of 91-93 ° C}

IR ^: 2210 / CN / i 1670 / CHO / cm ^-1} m / a 137 / M * / ·

Examples IV-XI. Method zbliys-white as described in Example H, but the howling EC ^^ tears ^d pol ⁱⁿ the 9dnl.y Uwione ^ ^ ^yd aldeh uo formula ^R ^ ^CH ° ^^^^ in a row ^and a wheel-letter pujące ^ ^sy

0 formula 13, with efficiency ^ i! 24-42%: Example 1 1 1 1 ^r1 1 1 1 1 T.topn. / ° c / 1 1 1 1 Partial NMR j at 1 1 2 and —-JL. 3 and - 4 IV 1 1 | 4-Br-2-oxygen 1 1 | 72-74 1 5.92 / 1h, s /, 7.12 (1H, s), 7.23 (RH, 41) V 1 5-Br-2-thienyl 1 1 143-145 5.88 / 1h, s /, 6.95 / 2H, m / J VI 4 - ^ .- 2 - 1 lenyl and f 112-116 5.91 / 1h, s /, 7.10 / 2H, m /! VII 2-oxygen 1 1 149-151 5.97 / lh, s / , 7.02 (Hm), 7.18), m / j VIII 5-Cl-2-oxygen Ł 1 153-155 5.85 (lH, s /, 6.80 (1H, d /, 6.93 / 1h, 1 / [ IX 1 2-furyl 1 1 1 1 139-141 1 5.80 (1H.s). 7.53 / iH, m / 6.38 (ll, m /, 6.53 (lH, m), [ X 1 1 5-Br-2-furyl 1 1 | 157-158 1 | 5.75 (lH, s /, 6.33 (lH, d (6.55) H.d / J XI 1 1 1 3-oxygen 1 1 1 146-148 1 1 1 5.80 / 1h, s /, 7.30 / 3H, m / J -----------

^Note: yjściowe kldJ ^hl yo ozorze R ^X is CH ^O tiannowo ^l lstępnJ, ^E and B can be prepared by standard methods analogous to those described for slnleJs-white description.

Example XII. 2.0 ml of a 2M solution of soybean hydroxide is added to 420 mg of 4 (Z) -6- (2,2-bis (tnfflmomethyl) -4-3-pyridyl) -1,3ddccksan-c: s-5-- while stirring. 10 ml - helium: methyl senate (G) 10 ml. After 2 hours, 40 ml of water are added. The solution is acidified with acetic acid and then extracted with ethyl acetate (4 x 20 ml). Combined extract.

The mixture is washed with saturated brine / 20 ml / and dried over MgSO ₄ . The solvent was evaporated to give an oil which was purified by flash chromatography eluting with ethyl acetate / hakaane / acetic acid (70-10.1 v / v) to give a white solid. It is rakkyataised from ethyl acetate / hakaane to give 246 g of crystalline acid 4 (Z / -6 / ~ 2,2-btβ / thiiflro-amyl / -43 / p..pidides / o / -1,3-dtok8aneciβ-5) -1H-Hakaano, mp 119-12O ° C, NMR 1.67 (1H, m), 2.29 (4H, m /, 2.51 (H, m), 4.22 (H, d, 3-11 Hz /, 4.45 / IH, dm, 3.1lHz /, 5.20 / Hm /, 5.50 / H, m /, 5.62 / lH, d, 3.1.5Hz /, 7, 40 (H, m /, 7.74 (1H, dm, 3o7Hz) and 8.60 / 2H, m / 1 microannaysis and found: C 49.4, H 4.2, N 3.2% j, and C17H17NO4F6 was calculated : C 49.4, H 4.2, N 3.4% µm / e 414 (M + H / +).

The necessary starting compound G is prepared by the following methods / and / 10 ml of 1M hydrochloric acid are added to a solution of 1.42% of 4 (Z) -6-4 / 72,2-dimethyl-4- (3-pyridyl-1-S-okoken) acid. The mixture is stirred for 2 hours in 16 mm tatrahydrofuran (THF). 40 ml of water are added and the pH is adjusted to 12 with 2M sodium hydroxide solution. The mixture was washed with ethyl acetate (2 x 25 ml), acidified to pH 5 with acetic acid, then saturated with solid sodium chlorine. The aqueous mixture is extracted with ethyl acetate (12.6 -8.0 ml) and the combined extracts of MgSO4 are dried. The solvent is removed by evaporation to obtain 1.113 ml of 4 (Z) acid 4 (Z) (yellow-methyl-8 -13-polyol). O-eye oil / H / in the form of spray oil, which is used without further purification. A sample of the compound, designated for enzyme enzyme, is purified by the fast c / Γommkoogβki and, for the purpose of arranging mθwanol / dichlormmwaaa / 1: 5 v / v / 1 NMRi 1.91 / 3H, mm,

2.23 / 5H. m /, 3.59 (2H, m /, 5.02 (1H, m), 5.35 (3H, m /, 7.30 (1H, m), 7.76 (1H, m /, 8. 45 (1H, dd, 0-4 and 1Hz) and 8.60 (H, d, 3-2Hz).

(11) 1.06 g of p-touennosiphinic acid aonohydrate is added to a solution of 1.H4gH in 25 ml of methanol and the mixture is stirred for 3 hours. 0.83 ml of fluid is added to the mixture and the mls are concentrated to a small volume. 20 ml of brine was added and the mixture was extracted with ethyl acetate (4 x 25 ml). The trained organic extracts are washed with 10 ml of saturated brine, dried with MgSO 4 and the solvent is evaporated off. The obtained oil is purified on the M> l_C route, eluted and put in aθtanoO / dichlonoawaaa / 1: 12 v / v / and the result is 1.044 g of 4 / Z / w β-pay-8 / smooth-7-hydrnkβ ^ tation 8- / 3- methyl pyramid (1): NMR (250), CCDC ₃ ) and 1.82 / 2H, m /, 2.16 (m), 2.44 / 4H, m /, 2, 91 (2H, b), 3.67 (3H, 8),

3.81 / 2H, d, 3 · 3Ηζ /. 5.20 (1H.d, 0 - 2Hz), 5.30 (2H, m), 7.33 (H, m), 7.79 (1H, m), 8.51 (Hm) and 8. 61 / H, mm.

(iii) To a solution of 995 mg of I and 0.59 ml of artefinylmine in 20 ml of dic / J ^^^^^ meth ^ nu, a solution of 0.32 ml of methβnontUionyl chloride in 2.0 ml of dichloromethane is added over the course of 10 minutes. The mixture is stirred for a further 1 hour and then diluted with 50 ml of ethyl acetate. The resulting mixture was washed with water (2 x 15 mL), 15 mL of saturated brine, and dried over MgSO 4. Evaporate into the solvent to obtain an oil which is purified by MPLC by adding mstanoo / dichloromethane / 1: 32 vol / vol / to give 886 mg of 4 / Z / -erythro-8-hydroxy-7- (aethylsulio-oxymethylene). -θ- (3-pridine) -4-octane (H) in the form of a brownish oil which is used for further purification. The sample of the compound, intended for analysis, is purified by means of the metannn / dli / lnromethane system / 1: 5 obb · /^./: NMR: 1.91 / 3H, m /, 2.23 / 5H, m / , 3.59 / 2H, m /, 5.02 / H, m /, 5.35 / 3H, m /, 7.30 / H, m /, 7.76 / H, m /, 8.46 / 1H, dd, 3 = 4 and Hz / i 8.60 (H, d, □ 2Hz / '.

/ 11 / 1.06 g of p-toUnosinanoic acid manovinacid is added to a solution of 1.114 g of H in 25 ml of methanol and the mixture is stirred for 3 hours. D ^ c ^^ Jw 0.83 ml of trislumine is added and the mles / aalaa are concentrated to mmas / volume. 20 ml of brine are eaten and extracted with style acetate (4 x 25 ml). The trained organic extracts are washed with 10 ml of saturated brine, dried over MgSO 4 and evaporated off the solvent. The obtained oil is purified by MPLC, by pouring in aetannn / dii / lonomwaa / 1: 12 v / v / and obtaining 1.044 g of 4/2 / -βΓ ^ ro-8-hydroxy-7- / łd -oxyyatwlo-8 - (3-pyridyl) -methyl-oxide / 1 / in the form of an oil: NMR:

/ 250 MHz, COCly: 1.82 / 2H, m /, 2.16 / 1H, m /, 2.44 / 4H, m /, 2.91 / 2H, b /, 3.67 / 3H, s / ,

3.81 (2H, d, 2 Hz), 5.20 (H, d, 3.2 Hz), 5.30 (2H, m). 7.33 (H, m), 7.79 (H, m), 8.51 (H, m), and 8.61 (H, mm.

163 045

Example XIII · Performs gel hydrolysis using a method analogous to that described in Example XII, but starting with 4 / Z / -6 - /? 2,4,5-cib / -2-pentafluoroetyyoo4- / 3-pyridyl / -1,3-diocaane -5-ylo_7hekeenianu ι ^ γΐυ. After evaporation of the extracts of the acidified reaction mixture, a colorless oil is obtained, which solidifies upon rubbing with hexane. After recrystallization of the solidified oil from the atyl acetate / haxane system, the acid is obtained 4 / Z / -6- / 72.4, 5th / - 2-pentafUuoroety / o-4- / 3-pididyl / 3 /, 3 / deokββn-5 / yl_7hekβe / owy with a melting point of 121-124 ° C, with an efficiency of 61%: NMR / 250 IMlz, OOLj / and 1.68 1.85 / Ή, η /, 2.30 / 4H, m /, 2.51 / ll, m, 4.03 / lH, d, 3 lllz /, 4.31 lH.d, 3-1lHz /, 5.21 / 31, m /, 5.46 (1H, m /, 5.35 (1H, b), 7.39 (1H, m /, 7.72 (1H, m / 1 8.58) / 21, ba / j mikroanallzai found: C 51.4,

^4, 5, N ^3, 3%: for ^ 7 ^ 8 ^ ⁴ ^: Calculated: C, 51, 6, 4.6 l; N, 3.5%: m / e ⁹ 6 3 / M + H / ^+.

The starting methyl aster is prepared by a method similar to that described in Example 12 / iv / but using pβntafluooprop / onaldβhyd instead of hθkθaflu / Γoacet / nu, 4 / Z / -6 - / * 2,4,5-ceβ / - Methyl 2-eentailuorottyl-4- (3-pyridyl) -1,3ddiocβan-5-yl-7hacoxate is obtained as a yellow oil with a yield of 59%: NIMR: 1.61 / lH, m /, 1.81 / lH, m /,

2.30 / 4l, m /, 2.53 (lH, m /, 3.66 / 3l, s), 4.02 (lH, dm, 0-lllz), 4.29 (lH, dd, 3-11, 1.5lz /,

5.21 / 3l, m /, 5.45 / lH, /, 7.34 / lH, m /, 7.68 / lH, dm, 3-7Hz / and 8.56 / 2l, m / ^: m / e 410 / M + H / *.

Example XIV. 3.0 ml of 2M sodium hydroxide solution, while stirring, add 218 mg to the solution 4 / Z / -6- ~ ”2, - deethyl-4- / Pr / ridyl - / - /, 3odlokoec-ci8-5oyl7_7hθktnnIon mf / lu in 10 ml of methanol. After 5 hours, 20 ml of water are added, the solution is acidified with acetic acid and extracted with st (3 x 15 ml) acetate. The combined organic extracts are washed with 10 mL of saturated brine then dried over MgSO 4. The solvent is evaporated off and an oil is obtained which is purified by means of rapid chromaJoygaJ and eluting with AT (LL) / hexane / acetic acid (70: 30: 0.1 v / v) to give 145 mg of the acid 4 (Z) -6- / ~ ^_ 2,2-diyl-4 --- ppiry / ylo / -lr3 / deocoane-Ci8-5yylJkhekoanoate in the form of a pale yellow oil:

NIM ?: 0.86 / 3l, t, 3 <= 7lz /, 1.08 / 3l, t, 3-7lz /, 1.66 / 4l, m /, 1.95 / 2l, m /, 2, 30 (4l, m /, 2.52 (lH, m), 3.84 (ll, d, 3-1 lt), 4.15 (lH.d, 3-lllz), 5.23 / 2l , m /, 5.40 (lH, m /, 6.32 (lH, brA 7.35 (lH, m), 7.75 (lH, dm, 3-7 ^^ ⁾ and 8.55 / 2l , m / m / e 334 (M + H / ⁺⁾ . After several weeks at 4 ° C, the oil slowly crystallized. ^P trituration of the solid with hexane gave crystalline material of melting point 72-77 ° C mikroanallza: atwltΓrz / oo: 68.2 C, 8.4 l; N, 4.2%: dle C / 1 ₂₇ wyllcz N04 / oo: C 68.4, l 8.2,

N 4.26%.

The necessary starting ester ιπθι / Ι ^ / is prepared as follows:

/ 1 / For a solution of 5.0 g of acid / 4 / Z / -6 - / “2,2-dimethyl-4- / 3-plrsryl // 1,3-dyokβa-ciβ-5-yyo_7 hexenoic acid / ow 50 ml methanol is treated with 3.74 g of p-toluθnotultonic acid monooodate. The mixture is mash for 4 hours then added to 75 ml of 5% w / v. sodium bicarbonate solution. The mixture is acidified with acetic acid and extracted with ethyl acetate (A x 20 ml). The learned extract is washed with 10 ml of water, then dried over MgSO 4 and the solvent is evaporated off. The remaining oil is purified by fast JhrymmJoygaJii, eluting with dichloromethyl / mβtanol / 92: 8 vol / vol / 1 yielding 4.20 g of 4 / Z / -Z-erythro-8-h / droxy-7-hydroxy kesetyls -8 - // - methyl pyrryl-4-octeneene as an oil which showed an NMR spectrum very similar to that of the diol produced in Example 12 / ii / / ii / 400 mg diol solution from step / 1 /, 293 mg aonovoyrate p-toUuenoeural acid, 290 microL of diethylocceitone and 383 ncrooltrimatyl orthoformate in 10 ml of acetonitrile are stirred for 4 hours. Add 20 ml of 5% oil / vol. sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate (3 x 26 ml). The combined extract / was washed with 6-15 ml of oats / ml of brine and then dried over MgSO4. The rinse aid is evaporated off and the remaining oil / oil is purified by rapid chrommJoyraJii eluting with AT (lu / hexane) 55: 45 v / v / to yield 218 mg of 4 (Z) -6- / ^- 2.2- diethyl-4- (3-pyridyl) -3, 3-thiokao (mt-5-yyo77hekθolane) in the form of a pale oil: NMR (250 MHz, COCl 3): 0.87 (3L, t, 3-7L), 1.06 / 3l, t, 3-7lz /, 1.49 / lH, m /, 1.61 / lH, m /, 1.75 / 2l, m /, 1.97 / 2l, m /, 2 , 30 (4L, m. 2.55 (1H, m, 3.65 (3L, 8), 3.31 (1H.d, J) andil,: /, 4.13 (iir.d, -1ilz), 5 , 20 [mu] H.m/,

5.28 µH.d. 3.2 [Eta], 5.38 (lH, m), 7.31 [lH, m). 7.70 (1H, d. 3 = 7 Hz) and 8.54 (2L, m / 1 m / e 348 µM).

153 045

Example XV. In a similar manner to that described in Example 14, but starting with 4 (Z) -6- [beta] -2,2-diisopropyl-4- (3-pyrididyl) -3, d-di3esan-eis-y-yl_7eaeeanean methyl. ,

W ^^ w ^ r ^ is quae 4 / Z / -6- ^ 2,2-dilzoplPlylo - / - / ^ - plridyl- / l /, 3-diocoac-ci8-5-yl7hek8θo in the form of pale yellow oil, yield 82 %: NMR: 1.04 (12H, m /, 1.59 (2H, m /, 2.13 (HH m), 2.28 (4H, m /, 2.50 2.96 (HH)) /, 3.82 (1H.d, C 11Hz), 4.18 (1H.d, 0-1lHz),

5.25 / 2H, - /, 5.42 / lH, m /, 7.33 / lH, 7.74 / lH, dm, 0.7Hz / and 8.64 / 2H, m / ι m / e 362 / M + H / ⁺ . ^{P k} t ^s it ilku ^d ° iac ^h retention in the ar ^ ^^ Tuiza ⁴ ° C, the oil slowly wykryytalizował. ^p o ^ ioz iciu ^H tanern e ^k u ^{k y} t ^k AOO substance sta'.iczn ^y and ^y is at a temperature of 74-62 ° nieoia ^p Ci mikroanoliza: Found: C, 69.1; H, 8.6; N, 3 , 9%: for C2 ₁ H3] _N0 ₄ 0.2SH ₂ O calculated: C 68.9,

H 8.6, N 3.8%.

The starting astai in ^^ is cooked in a manner similar to that described in Example 14 (ii), except that 2,4-dlmatyl-3-pθotaooo is used instead of diethylkathone. The result is 4 / Z / -6 - / "2, 2-diisopiopy1ο-4- / 3-ρ1ιυ0υ1ο / -1, 3-0coks8n-cis-5-yl_7aθkβenate in the form of pale yellow oil with 44% efficiency: NMR / 250 MHh, COCl-i): 1.07 (12), m /, 1.57 (2H, m), 2.13 (HH.m), 2.30 (4H, m), 2.53 (1H, m /, 2.96 (HH.dm, 3.64 (3H, s), 3.80 (1H, dd, □ nil, 1.5 Hz), 4.14 (HH.dm, 0 = 11Hz) , 5.20 (1H, m), 5.28 (1H, d, 0-1.5Hz), 5.35 (1H, m), 7.30 (Hm), 7.20 (1H, d, 3 = 7 Hz / and 8.55 / 2 /, m /: m / e 376 / M + H / *.

Example XVI. In a manner similar to that described in Example I, but using as aldehyde 2 (methyl-2- (4-mttylos) phenylphenoxy / pilpanθl, the acid 4- (Z / -6- / / 2,4,5-cis / -2) is prepared. - / jmatylo - / - / 4-m. ty lot ul phonylphenolky (ethyl-4- (3-pyridyl-1,3) dioJxan-5-yl7haxene in the form of an oil with a yield of 2C%: NMR: 1.45 / 6h, s /, 1.8-2, 45 (7H, m /, 3.2 (3H, S), 3.95-4.1 (2H, -), 4.9 (1H, s), 5.15-5.45 (3H, m /, 7 , 2-7.85 (6H, m /, 8.45-8.5 (2H, m).

The necessary aldehyde in / is obtained in a manner analogous to that described in the connection with Example 19, starting from 4- (methylthyl) flonyl, which is converted into 2-methyl-2- (4-) methylthioxy / ethyl pyropionate / oil, 20% efficiency: NIM ?: 1.25 / 3H, t, 3n7Hz /, 1.6 / 6H, aj, 2.45 / 3H, s /, 4.25 / 2H, q, Jo7Hzz, 6.75 -7.2 / 4H, - / J · Eatei this is oxidized with the acid ^^ ch ^^ and ^ c ^ t ^ c ^ r ^ and ^ c ^ e ^^ c ^ v in dichloromethane in the environment and gives, after conventional treatment, 2-methyl-2- (4-methyl-3-sullionoxy) ethyl proplonate / oil, slow-drying, yield 92% NMR: 1.25 (3), q, 3 = 7 Hz). 1.65 (6H, s), 3.0 (3H, s), 4.25 (2H, q 0-7Hz), 6.9-6.95 (2H, m), 7.8-7.85 (2 /, m / 7), which is then subjected to a reduction with DIBAL, to give 2-methyl-2- (4-n]-tylsufylolyl-eyed) propanal as a solid and a yield of 66%; NIM ?: 1.5 / 6H, s /, 3.05 / 3H, s / 6.9-7.0 / 2H, m /, 7.8-7.9 / 2H, m /, 9.8 / lH, s /.

Examples XVII-XIX. By a procedure analogous to that described in Example 1, but using the appropriate aldehyde, the following is prepared:

Example XVII: acid 4 / Z / -6- / 72,4 _ł 5-cls / -Z - // - ^ 2-ιtθlok / yf enoksy_7-l ~ me tlloe tyło / -4- / 3-ρι ^ 1υ1ο / -1,3-dl / lnas-5 “ylo_7heksnlowl in the form of an oil, solidifying after some time, whereby the substance is obtained from! Υ0θ1οο0ο ^ 40%: NfMR: 1.35 / 3H, s /, 1.40 (3H, s), 1.55-1.80 (2H, m), 2.20-2.555 (5H, -), 3.78 (3), 3.95-4.25 (2H, -), 4.80 (1H 3). 5.10-5.50 / 4H, m /, 6.80-7.10 / 4H, m /, 7.40-7.75 / 2 /, m / and 8.45-8.60 / 2H, m /, starting with Z / -ethyll / Z- / 2-mttoktlphenoctl / pΓoplnβlu |

Example XVIII acid 4 / Z / -6- / / 2,4,5-cis / -2- / l ^ ~ 2ime tyło e ^ r ^ oxy _ ^ -: i - ^^ tyloethyl / -4- / 3-ριγυ1υ1ο / -1,3-dltloas-5-yl_7keksellWl in the form of an oil that solidifies after some time, whereby the solid is obtained from the excretable 15%: NIM ?: 1.40 / 3H, s /, 1.45 / 3Η, ^, 1.50-1.80 (2H, m /, 2.25 (3)), 2.15-2.60 (5H, m), 3.95-4.25 / 2H, - /, 4. 85 / lH, s /, 5.10-5.50 / 4H, m, 6.90-7.15 / 4H, - /, 7.10-7.75 / 2H, m /, 8.50-8 , 60 / 2H, m /, starting from 2 - ΘΙι / ο / ZZ / - ^m etylotθnoksl / pΓoplnalu;

Example XIX: acid 4 / Z / -6- / / 2,4, ^^ 1213 / - ^^ 2-12-n liiio ^ -me t yloe nπoxl ^ -1 - etithi1o / -4- / 3-pi yydy lo / -1,3-dioxane-5l / 11tkseel in the form of an oil, which solidifies after some time, and then the solid is obtained with a bearing capacity of 28%) NiM ?: 1.45 / 6H, s /, 1.50 -1.80 / 2n, m, 2.35 / 3 /, //, 2.15-2.50 / 5H, - /, 3.90-4.20 / 2h, m, /, 4.80 / lH, s / 5.05-5.50 / 3H, - /, 7.10-7.70 / 5H, m /, 8.45-8.60 / 2H, - /, starting with 2 - eey1ο- 2- / 2-οιιoo-4-methylphenoxy / piipmalu.

163 045

The necessary starting aldehydes were prepared by the following methods (XVII) 2-methyl-2- (2-methoxyphenokey) propanal, prepared as an oil, NMR: 1.35 (6H, a).

3.75 (3H, a (1) 6.80-7.25 (4H, m), by a method analogous to that described in Example 1, but using 2-methoxyphenol 1 1, lddchhloro-2-hddrkxy22-matylpropane / XV1H (2-meyyl2-6-methylfendey) propanal and prepared as an oil, NMR: 1.45 (6H, e), 2.25 (3H, j (1 6.60-7.20 (4H, m)) starting from 2-m <Jtylphenol 1 1 · l-daehrooo22-hydrohay-2mθtyll-plopan 1 using a method analogous to that described in Example 1 | / XIX / 2 - θlyl-2- / 2-nloro4 - oetyrflenokky / prrpenβl «/ 1 / A solution of 11.48 g of 2-nltfo-4-elethylphanol in 50 ml of 1,3-dimθtyl-3,4,5, 6-ttahydro-2 (1H) -pyrimidinone / DMPU / a chilled gel to 5 ° C and treated portionwise with 3.27 g of sodium hydride in the form of 55% w / w. dy8ppaoki in mineral oil. The mixture was stirred at room temperature ^toilet ble ^g in 2 ^hours, then ozię ^ ^d Sia and 5 ° C and for ^d AJE ^SIU 13.15 ^{g of 2-bromo-2-yl} mθt oporpionianu et ^y acetate. Me ^{S and} nin ^e o ^g rzawa ^SIU at oltota 1W ° C for ^{18 g} odzln then OZL ^^ e ew to room temperature, poured into 1 mixture of aqueous lM sodium hydroxide solution and ethyl acetate. The organic solution is separated and washed two times with 1M sodium hydroxide solution, then dried over MgSO 4 and concentrated. The residual oil was purified by rapid chromorraph fi krhunowθt using a mixture of ethyl acetate and hexane (increasing from 5 "95 v / v). to 10:90 v / v / to yield ethyl 2-methyl-2- (2-mlo-4-mathyl) / ethyl porionate in an amount of 4.48 g as an oil: NMR: 1.25 / 3H, t /, 1.60 (6H, s), 2.35 (3H, s), 4.25 (2H, q), 6.8-7.6 (3K, m).

(ii) A solution of 4.47 g of 2-methyl- (2-nitoo-4-mofenOylphenocty) ethyl propionate in 50 ml of toluene is cooled to -78 ° C and 11.3 ml of a 1.5M solution of isobutyrgglass hydride are added dropwise / 01 BAL / in toluene. The mixture is stirred for 2 hours and then about 4.4 ml of OIBAL are added until completion of the reaction as indicated by tlc. The reaction is quenched by adding an aqueous solution of amine chloride and ether. The resulting mixture is clarified by filtration over rhoamic earth. The organic phase is distilled off, dried over MgSO 4 and concentrated to an oil. After purification by rapid chrommaoofi cohumnowtt, elute a mixture of increasing concentrations of ethyl acetate and hexane from 10:90 dc. up to 15:85 rb./vol. there are obtained 2-methyl-2- (2-n-trro-4-methylphenokey / propanal) in the form of oil in the amount of 1.89 gj NMR: 1.45 / 6H, e /, 2, 35 (3H, s), 6.8-7.6 (3H, m) and 9.85 (1H, s).

Example XX. Solution 0.331 g of acid 4 / Z / -6- / ~ / 2,4,5-cks / -2- / 1 - / '' m-ιnθtok8ytenoxy ^ -1-methylethyl / -4- (3β-plridyl) -1,3ldSok3anyhryl ^ hsαsantwegr in 6 ml TWO maintained ^at 5 ° C, a task ^ ^e ( ^{'216 mg} hydride in oil Sa ^d u as a ^5% weg./wa^ ° dy8pθa8S ^and mineral oil and 0.3 mL etanotulu, and The mixture is heated at 130-135 ° C for 3 hours, the mixture is cooled to room temperature and poured into a mixture of ethyl acetate and 1M aqueous sodium hydroxide solution. The organic phase is separated off and extracted twice with sodium hydroxide solution. The combined aqueous extracts washed with dichloromethane and acidified with acetic acid to pH 5-6 The mixture was extracted three times with chlorormmafane and the combined extracts were dried over MgSO 4, then concentrated to an oil. After purification by rapid chromafolraffi cohkmnm, elute the mixture. ea ^^ lu and dichlolomatan / 3: 97 to 10:90, calc./vol./ the obtained acid is 4 / Z / -6 / "/ 2,4,5-JIsS-2" / 1- / ^- 2- hydroc skfθaoklyk7-l-mθteOohtalo / o4- / 33-lyridyl / -1 · 3-dioxαn-5-yl_7 htxane in the form of an oil which solidifies to give 0.253 g of a solid: NMR: 1.35 /3H.S5/, 1 , 45 (3H, s). 1.55-1.80 (2H, m), 2.20-2.55 (5H). m /, 4.00-4.35 / 2H, - /, 4.80 / lH, β / τ 5.15-5.55 / 3H, m /, 6.70-7.05 / 4H, m / , 7.40-7.75 (2h, m) and 8.50-8.65 (2H, m).

Example XXI. The acid 4 / Z / -6 - / "/ 2,4,5-ci8 / -2- / 2E / is prepared by a method analogous to that described in Example I, but using the aldehyde 2-mtoxycalpha. 2-mtokkyphenyl (ethylenyl), N-pyridyl-1,3-dioxane-5-yl-oxan as an oil which solidifies to give a solid in 18% yield: NMR: 1.60-1.80 / Z H 4 m /, 2.15-2.65 (2 SH 3 R N, 3.85 (3 ","), 4.00-4.30 (2H), 5.10-5.50 / 4h. m /, 5.30-6.40 (1 H, m), 6.85-7.85 (7H, m /, and 8.50-8.65 (ΣΗ, -).

163 045

Example XXII. Reaction of an aldehyde / ketone, acid catalyzed, opium in any preceding examples can also be performed atoaujęc acid 4 / Z / -6 ^ ^_ 2,2-diethyl-4-33ppiryyylo / -l, 3-diakaan-Ci5-y- yl (kekeezic) described in Example 14 / instead of the 2,2-dimethyl derivative (compound / A) described in part (v) of Example I). Usually, very similar yields of compounds about I.

Example XXIII. 0.468 g of naphtha aldehyde and 0.22 g of p-toluenesulfonic acid are added to the solution of 0.305 g of quaeu 4 (Z) -6 - N-2,2-di-methyl-4 (3-pyridyl) -1,3dDZok8ancis-5-yl / haxanoic (compound A described in example 1) in 10 ml of ecetonitrile under argon. The mixture was heated to reflux for 1C hours, then allowed to cool. 10 ml of ethyl acetate are added and the mixture is extracted with 60 ml of 2M aqueous sodium hydroxide solution. The basic extracts are acidified with acetic acid to pH 4 and extracted with 90 ml of ethyl acetate. The combined organic extracts are dried over MgSO ₄ , concentrated to give Hey, which is purified by rapid chroma to quinum elution eluting with mθnol / dichlosomethane / 1: 10 to 1: 5 v / v /. Obtained 0.224 g of 4 / Z / -6- / 72,4,5-cis / 22- / niftyl-2 - / - 4- / 3-pirydylo3 ^_ l • o-dian-an-cis-5-yloa7hekionoaegz as a solid melting point 13 ^C -142 ° C. NM ^: 1.74 (2H, m /, 2.2 ^c (4H, m), 2.64 ( ^H H, m), /, 1C2), 3) / 2H, m /, 5.27 (3H, m /, 5.43 (HH, m), 5, CC (1H, s /, 7.33-7.68 (4H, m), 7, C5-C, 02 / 5H, m / i ^c , 5 ² - ^c , 63/2 ^H , m / ^j m / e ⁴⁰⁴ / ^M + H / + ^j microannlysis: found: C 73.5 ^, H ⁶ , ^3, N 3.3% ^j Ha ^ 25 ^ 25 ^ 04 ' ^0.2 5 ^h 2 ° '' ylucine: C 73.6, N 6.3, N 3.4%.

Example XXIV. By a procedure analogous to that described in Example XXIII, but starting from 3-banzyloxybenilldθhyll, the acid 4 / Z / -6 - // 2,4,5acss222- / 3-aθnzploxyfnyPoZ “4- / 3-plrpdyl / -1, -ldzok9en is prepared -ail-5-ylo_7heksanowy as a colorless solid tamppa8turie ¹²⁵ - ^12C ° C and wydajoścj ^4% 3: ^{1 NM R,} 75 / 2H, m / ^{2 »2C} / 4 ° C / ^2, 55 / LHM /. 4.12-4.28 (2H, m), 4.85 (1H, m), 5.12 (2H, s), 5.27 (2H, m), 6.98-7.75 (1HH. m / i C, 5C / 2H, m /: ^ e 459 (M + H):: found: C 72, C, H 6.4, N 2.9%: H, C 18 H 8 H 8 NO, calculated: C 73.2 , H 6.4, N 3.0%.

Examples XXV-XLV. Using an analogous procedure to that described in Example I, but with ocJpowi ^ cholzj-adnieijo HDA ^ ^ wzoi IJU of the RuHO acid ^{and l} l ^k ¢ ιksanoha sanowa ^g of ^A, prepared Follow these compounds ow ^ (13 ^ ria.

^{P r} ykład ^{χχ V, R} n 3 '- / 4-cyJanobθni ^{IP with} 8yPfθny ^p: wydiie ^l on ^{y p} ostaci cula st ^A deck ^g oo m.p. ¹ 49 ^ 1 ^ i ^ ^o0 Cj ^PART steak with ^p NWR 5.70 / H, s /, 6.95 / Jm /, ^7, 2 ^C / 4H, m /, 7.55 / 2H, 1 /, 7.65 / 2H, d /, 7.33 / lH. 1 /, C, 53 [ ^mu ] H, m /, C, 62 [ ^mu ] H, <RTI ID = 0.0> s / j. ^R = l-nafjl: ^p wydzlalzn as a solid, m.p. 1-172 ¹ ^ ¾) ai ^ę steak with ^p ?: ⁶ NM ³ / H, S / ^7, 32 / jLHm / ^7, 52 / 3 ^ 1 ^ / ^, 7, ^C5 / ^^ / ^{, C,} 2 ² / lH, s /, C, 52 _lH, d /, C, 63 / lH, s / j

Example XXV ^pI . ^R ^ n ^^ - cyano-8 NO anzyloksypfθny ^{b p:} ^ DLLs ^{in one} branch ^y jstaci solids having a melting point of ¹⁶ 2- ¹⁶ 4 ⁰ Cj cięstkoo ^p NMR: ^{5, 6, 9} / lHj / ^6.97 / ^ 2 ^, ⁷ , 36 (Hum), 7.52 (4H, m), 7.70 (3H, m), C, 53 (2H, m / j

Pri ^pk order OTIII. ^{R b} and 22 eiiyloks ^en ai ^Q1: c ^ ¹ ^ 2LA and from ^{y p} ostaci ^μι) ι solid concerning this tojienia Ul-n-C: aięstkow ^p ?: ^6.1 NM 5 / H, S /, 6 R ³ (Ih, ¹ ), ^7.05 (1H, t), ^7.31 (7H, m), 7.7C (2H, s), C, 51 (1H, d), C, 5C (1H, s /.

Example XXIX. ? = ^^ nzyloxyphenyl ^; wydzieb ° C in the form of a solid, the ^y ^^ ^ θr lria mp 0- ^ ²⁰⁴⁰ ^ ai ^ę steak with PTT ^y ?: ^5, 72 / H, S / ^7, 02 / ^{2H, d} /, ^7,1C / lH, m,

7.40 (H, m), 7.72 (1H, s), C, 4C (1H, d), C, 53 (1H, s).

When ^k order XXX. R ¹ o / - / 3-piP ^d dy ^from omθtzxyphenyl ^; ^ c ^ ^a 2LA ^one branch in the form of ^white solid, m.p. tempe nature 174-1770cj częstkowy ?: 5.62 NM / HH, s /, 6.93 / 1 2R /, 7.25 / 2H, l /. 7.43 (2H.1/). 7.69 (2 ^ 8), C, 50 [mu] m.

Example XXXI. = ⁴ -fanoxyfanyl ^: precipitate as a solid, mp. 2-144 ° C: partial NMR: 5.72 (1H, s), ^7.07 (5H, s), ^7.35 (3) ^ /, ^7, 55 (2 ^ 6), 7.7C (Hm), C, 57 (2 ^).

Example X 1 X ^X I. ^R * = N-phenoxy-enyl ^: higher in the form of a solid hail, m.p. 130-132 ° C, frequency NM: 5.72 / 1h, s /, 7.07 / 4H, m /, 7.35 (eH.s, 7, C2 (Hm), c, 55 (2H, m ⁾ .

163 045

Example Χ3ΧΙΙΙ. R ² »3- ^/ ^ 3 ^ - ^ f) i.ryd'yl ^ netokt ^> y / fen> yi.j isolated in the form of a body

6tałego at a temperature that ^p nlenia ¹ 04 ~ ¹ 05 ° Cj NMR: 5.70 /lH.s/, ^6, 98 / H, m /, 7, 8 ¹ / H, o /.

7.33 (4H, m /, 7.71 (1H, o), 7.88 (1H, m), 8.55 (3H, o), 8.82 (H, o).

Ex ^yk order ^X XXIV. 2- ^r2 / 4ccyJanobanzyl.okk ^s / f any ^{y: l} wydzle as a ^white solid, m.p. 159-162 ⁰ tanienia Cj partial NMR »6,1.5 / H, S /, ^6.88 / H, ^d /, 7.09 (III.t), 7.37 (21.0), 7.47 (21, d), 7.58 (2H, d), 7.77 (21, V. 8.55 (2H). m /.

^example XXXV. R ² = ² - / ^3-k pryydylome is sy / fen ^{s] l} secreted .i on ^y as a solid 9tała ^g oo at a ^p nieni.a ¹³ 1 ¹³ 5 ° C "partial NM ^{y (j} R ^{6, 1} 5 (lH, s), ^6.92 (lH, ^y ), 7.0 ⁸ (lH, t), 7.30 (3H, m), 7.72 (3H, o), 8.60 / 4H , m /.

^p rz ^yk order ^{χχχ νΐ. r2} o ⁴ - ^b θnzy ^d okkyd3 - ii rophenyl ^{; in} ^ ^(l ^ zlβ ln ^{y p} ostaci body standing ^l E ^g oo ^ pnieni.8 at ¹⁵ 0 ~ ¹⁵² ° ^C partial ^y j NMR 5.70 / H, S /, ^7.12 / H, ^y / , ^7.38 (6H, s), 7.73 (21.0), 8.04 (1H, d), 8.57 (2H, d).

^p y ^y EXAMPLE ^ΧΧ χ ΙΙ. ^r2 and ³ - / ^{- l} ly nnaf ometl ^k sy / ^{phenyl: p} oataci Wydz in solid, m.p. ¹ ^^ ~ ¹¹⁷ ° C "of particulates ^y NMR: 5.70 / H, S /, 6.52 / H , m /, 7.03 (1H, m /, 7.18 (1H, d), 7.33 (3H, 0), 7.47 (3H, 0), 7.60 (1H, d), 7 , 81 (3H, 0), 8.05 (H,), 8.55 (2H, 0).

^{see /} example ΧΧΧΧΙΙΙ. R a ³ - / 2 ^ -cJime toltsybann ^ dky / feny ¹ . j ¹ in the separated ^p ostaci solid of melting topnieni.a 5 ³ -5 ⁴ ° Cj ^PART NMR steak with ^y »5 ⁷² / H, S / ^6, 82/2 ^ ^{^,} 7.00 /lH.m /. 7.15 (2H, 0.1), 7-31 (4M, m /, 7.82 (1H, m), 8.57 (2H, m / _; ^{example χ} ΧΧΙΧ. ^r2 = ^^ - ^ y ^ pid methoxy / lfanyl: secretion in ^L on ^y ^ os ^p latin solid, m.p. ~ ¹¹ 5 ¹¹ 7 ° C | Part C and C in ¹ NMR ^"6, 4 ¹ / H, s /, ^6.87 / H, ^d /, ^7, 0 / H t /, 7.12 / Ih, 0 / 7.60 / 7H . 0), 8.6 (2H, 0).

^p y ^{y χ} EXAMPLE 1 .. ^R N-naphthoquinone chlorool. Ayl: ^a ^ l ^ ^l branches ln ^y as gave a solid of m.p. araturze TEO ^{p 1} 0 88- ¹⁹ ° C: partial NMR ^y 6, ⁷ 3 / Hj / ^{7 2} / lHjs / ^7, 46 / 21.0 7 ^{^,} 62

7.75 (3H, m /, 8.53 (2H, o), 9.02 (1H, d).

Example XLI. R and 2- / 2-pldydylooetoksy / fenylj isolated as solids ^g oo ^ goes live at 86-88 ° C: ^PART steak with NMR ^{y "6, 1} 8 / Hj /, ^{6, 9} 2 / H, d /, ^7, 05 / H, t /, 7.18 / H, t /, 7.29 / 2H, 0 / 7.45 / H, d /, 7.57 / H, d / 77.6 / 2H , dd /, 8.55 (31.0).

^p y ^y KLED ^{χ Ι_ΙΙ. r2} and ^^ - ^ ni obanz oxy ^ / ^ j nylon secretion ^ n ^ ^{1 p} ostaci solids at a temperature pnien ^ ¹ ^ 66 ^ ¹⁶⁸ ° Cj of particulates NMR ^y »6.14 / H, S / 6, 88 / H, ^d / 7 ^ ¹ / ll t /, 7.32 / 21.0 / 7.50 /2H.d/, 7.76 / 21.0 / 8.16 / 2H, about /, 8.59 (2H, o).

^p rz ^yk order ^{χ Ι-ΙΙΙ. R} 3 and ^{b 4} enzyloksy- -metoksyfeny ^{y »Faculty]} .ln ^d in the form of bodies ^as t ^{and L} e ^g oo at tanienia ¹ 28- ¹ 30 ° Cj częstkowy NMR» 5.6 ² / H, S / 6 ^.9 0 / lH, d /, ^7, 12 / 2H ^,

0), 7.44 (6H, o) (7.68 (1H, o), 8.55 (2H, o).

^p rz ^yk order ^X ^ L and ^{V r2} · 3/3-c ^Y Jano βnzylok9yy ^b-4-d oetoksy θny ^dj y ^^ ^ ^zi.e] he ^ ^y ^ s ^ of the solid melting at ¹ 48 ~ ¹ 4 ⁹ ° C | ^PART NMR steak with ^y »5.63 / H, S / 6 ^ 2 / H ^ /, 7.13 / 2H, o /, 7.32 /lH.m/. 7.45 (1H.m, 7.58 (1H.m), 7.68 (21.0). 7.80 (1H, s), 8.55 (2H, o).

^p y ^y EXAMPLE XLV. ^{R b} and 4- anzyllksy-3-c ^y y anofenylo: ^l secreted on ^those Ala ^{y s} t ^{r a g a-oo} faoperaturze tanienia ¹ 64- ¹ 65 ° Cj of particulates ^y NMR: 7.4 ¹ / 7H, 0 / ^, 7.78 (3H). ^ ^, 8.8 ⁽ lH.dd), 8.55 (lH, d).

New starting tanzaldetyty of the formula ^R CHO prepared prin ^ iiczo takio stjo ^ o ⁰ oijólny way, outgoing connections with the corresponding hddlokydbeπzaldβhydu and the appropriate benzyl bromide or / brl0olay1o / plrydyπy. These starting compounds are heated in the presence of an excess of anhydrous potassium acetate in afylumethyl ketone to boiling point and reflux for 2-18 hours, until the reaction is complete, as confirmed by thin layer chromatography / TLC / on silica. The product is then isolated by concentration of the superπafaπf in the reaction mixture and the residual material is purified rapidly as eluent with hexane / ethyl acetate up to 30% v / v. The resulting benzalda ^hydd of formula ^{R 2} c ^ho used mooliwie s ^ybk o. In particular they show seq ^ ^ ujce Majesty / 1 / a-HRM-cyannobenzyloksy / benzaldehyde fampprθtur8 mp 96-97 ° C j ^k Jząst head NHR 5.18 / 21.8), 7.24 (1H, m), 7.50 (51.0), 7.68 (2H, d), S, 9e (Hs).

/ 2/4 - / ^ zlc ^^ a π n xy enzymes, ^ nz ac ^ e hy d, fao ^ er ^ melting turl 1O5-1O6 ° C: frequency NMR: 5.23 / 21.9 /, 7, 06 (2H, d), 7.54 (2H, d), 7.69 (21, d), 7.86 (2H, d), 9.90 (1H, s).

/ 3/2-baπz ^di o ^k a ^yb θnzal ^d e ^hyy , temperature 4 ² -4 ⁴ ° Cj and ^ in ¹ NMR »5.20 / 2H, ^y ' ^, 7.03

163,045 (2Η.β/, 7.44 (6Hm), 7.86 (H, m). 10.58 (lH, s)

/ 4 / 4- / 3-pirydylometokey / ^{benzaldehyde,} m.p. ⁷⁵ - ⁷⁷ ° C, a partial PTT ?; ^5.16 (2H, a). 7.02 (2H, m), 7.30 (Hm), 7.76 (3H, m). 8.63 (2H, m /, 9.95 (Hm).

/ 5/3/3-pr ^{rice yl} mmatoka y ^y / ^{yd benzaldeh,} the temperature goes live ^48-50 ° ^ Cj partial ^NM? J ^{5, 09} / 2H, s /, 7.47 /5H.m/, 7, 70 [mu] H. M, 8.47 (2H, m), 9.90 [mu] h, b /.

/ 6/2 ^- / ^y Use 4c _and noben ^zy Yoksa ^{y / benz} lde ^hyd, m.p. 102- ^{10 /} ° ^{C ±} stko part j ^{in the} y ^NM?:

5.28 (2H, s), 7.01 (2H, m), 7.55 (3H, m), 7.70 (2H, m), 7.88 (Hm). 10.55 µH.s/.

/ 7 / 2- / 3-ρ1 ^ @ Πιηθΐoks ^y / benzalde ^{hy d} ^ goes live temperature of ⁵⁸ -5 ° ^C · ^{9/8/4 with a key-benzyl-3-hyd nitoobenzalde, m.p.-86} and - ⁸⁸ ° C, part ^± stkowy ^NM? 5.3 ⁴ / 2H, s /, 7.24 / 2H, m /, 7.42 / 4H, m /. 8.03 (H, dd), 8.37 (1H, d), 9.93 (1H, e).

/ 9/3 - / - aaft ^of lmeetkksybbenzalde ^hyd, m.p. 6 ^- -6 ⁴ ° ^{C ±} j man stkowy ^{NM? 5,} 5 ⁵ / 2H, s /, 7.27 / Hm /, 7.52 / 7 H m /, 7.87 (2 H m), 8.03. H H, J, 9.98 (5).

(10 / 3- (2,5-dimethoxybenzyloxy) benzayyehyde, produced as an oil: partial NM ?:

5.28 (2H, s), 6.83 (2H, d), 7.05 (Hm), 7.26 (Hm), 7.45 (3H, m), 9.97 (1H, s).

/ 11 / S- ^ ^^ ppir mmstoksy / benzalds ^hyd, m.p. ^y 3 ^7- l40 ° ^C cząetko j ^{y N} MR:

5.33 / 2H, s /, 7.20 / 2H, m /? 7.52 / 2H, d /, 7.71 / 2H, m /, 8.58 / 2H, d /, 10.48 / 1H , 8 /.

/ 12/2 / r ^s 2pplΓ ^yl omθtoksy / bθnzβldθ ^hyd, m.p. 67-6 ° ^{C 8 ±} j man stkowy ^{NM?: 5.32} / 2H, s /, 7.06 / 2H, m, 7.25 (lH, m), 7.53 (2H, m), 7.75 (lH, m), 7.84 (lH, dd), 8.61 (lH, d), 10.62 (lH, s).

(13 / 2- / 4-nitrbnzyl Hxy) benzaldehyde ^, mp. 110-11 ° ^Cj partial NM ?:

5.31 (2H, s), 7.0 (H.d). 7.1 (1H, t), 7.59 (3H, m), 7.88 (1H. Dd), 8.28 (2H, m), 10.36 (1H, s).

(14) 3-benzyoxy-4-m-stoxybsnzaydehyde, produced as an oil: partial NM?: 5.19 (2Hs), 6.99 (H, m), 7.38 (7H, m), 9.82 (1H) , s /.

/ 15/3/3? ^B enz ^y Jano ^yy of ^k s ^r / ^b -4mmθtoksy snza ^yd sh ^YD imperatura mp 113-'114 ° ^C, mol wt j ~ O ^co NM ?: 5.20 ^ Hs / 7. O2 (lH, d), 7.42 (lH, d), 7.49 (2H, m), 7.65 (2H, m), 7.80 (lH, m), 9.83 (lH, s /.

/ 16/4 ^{s-benz-3-ylksy} cyJanobenzaldshy ^d, topnien temperature of 117-118 ° ^ Cj partial N ^MR:

5.32 (2H, s), 7.14 (1H.d), 7.42 (5H, m), 8.03 (1H, dd), 8.11 (1H.d). 9.88 (lH, s).

Examples XLVI-XLVII. In a similar way to that described in example I, but starting from the acid 4 / Z / -6 - / "/ 4S, 5R / -2,2-dimethyl-4- (3pplryloyl) -1,3ldlox-5-r-yl_7keSsθnowθgl and 2 -methyl-2- / 2-nltro-4-methlaspheneSry / plppanal and 2- / 4-methoxrasnlxy / -2-methylpropβnβlu, respectively, are produced:

Example XLVI: acid 4 / Z / -6 - ^ "/ 2S, 4S, 5R / -2 - ^" l-me tyrooly / 2-nl tn-4-methylphenxy / stylo / -4- / 3-Pyryyyloy -1,3odloksan-yl / o / hθksnlowy, as a solid, in 25% yield, ^with _q _7 - ^117, 6 ° / EtO c ^ ^0, 635 / ': 1 H NMR: H45 / ^ 6 s / ^{1 ,} 5-1.75 / 2 ^^ 2 ^, 2-2.4 / 8 ^ m, 3.9-4.2 / 2H, m /, 4.8 / H, s /, 5.05-5, 5 (3H, m /, 7.15-7.6 (5H, m /, 8.4-8.55) 2H, m / i

Example XLVII: acid 4 / Z / -6 - / "/ 2S, 4S, 5R / -2- / I- / - ^ - m 2 - oxy phenols, n - N - 1-methylethyl) - 4- / 3 -ρ / υ / υ1ο / -1 .S-dioxane-y-olo_ / ehel ^^ new in a poet of solids, with a yield of ² 8% ^, with ²⁵ / ^ <_7 _D -122.9 ° / EtO ^ c 0 ^ 9/1 NM? ^Y 35 · / 3l, s ^/, ^ 4 / 3H, s /, ^{1, 55-1,} 8/2 ^ m, 2.2-2.6 / 5H, m /, 3.75 / S ^ si /, -, 9-4.2 (2H, m), 4.75 (1H, s), 5.05-5.5 (3Hm), 6.75-7.7 (6H, m /, 8.5-8.6 (2H, m /).

The optically active starting derivative of 2,2-d-mstyl -, d-dioxanehθSsSlowθgo is produced by the following ^^^^ m o-10SO / s-:

/ 1 / 23.9 ml of a 1.53 M solution of butyllithium in hexane are added to a solution of 4.68 g of Sty-Z-isopropyl-2-okeazollrinone in 75 ml of dry THF, cooled to -78 ° C under agrlse-. The mixture is left to the ^d of warm ^y o ^{- about} 5 ° C, part of ^y m MIEI ^Si by -0 minutes. Seq onownie ^p is not ^{p -} ίeozasls ^± oziftua the ^Y -7 ⁸ ° ^C and a solution of ⁴ 33 ^g of 4- Stranger ^ ^p ssinoilu in 10 ml of dry THF. After addition the mixture was stirred 6ią at -78 ° C -0 minutes, after which leaves are heated by ^{a d y} o ^- 2 ⁰ ° C. ^The DD are ^ble 20 ml sao CLNE ^{g r} l cfilorku Mosu solution and extracted with ethyl acetate mixture SIA / 3 x 100 ml /. The combined organic phases are dried over MgSO 4 and concentrated. t: alumina is purified by rapid column chrommtooreaphy, eluted with eorl acetate / hxas / 20: 80 oib./obj ^/ and obtains ^ S / ^ - isopropyla - / - / 4-pentnolloloxazolidys-2-one / A / in the amount of 6.34 g for the poet, oil NM?: 0.850.95 / 6H, m, 2.3-2.5 / 3H, m /, 2.9-3.2 / 2H, m /, 4.15- 4.5 (3H, m /, 4.95-5.15) 2H. m

5.75-6.0 / Π, m /.

To a solution of 6.28 g of A in 110 ml of dry dichloromethane, 32.7 ml of a 1M solution of dibutylboron trifluoromethanesulfonate are added, cooled to 5 ° C under argon, then 6.25 ml of diisopropylethylamine are added. The reaction mixture was stirred at 5 ° C for 30 minutes, and c ^{zym of} Zia and a ^{b SIU to -78} ° ^{C. 3.1} ml of pyridine carboxaldehyde are added dropwise. The mixture is stirred for 30 minutes at -78 ° C, then allowed to warm for 30 minutes. -5O ° C. The cooling bath is removed and si.ę mixture was stirred rea ^k c ^y jn ^E in the room temperature for 2 hours. The mixture is then cooled to 5 ° C and 11.5 ml of 30% w / v are added. aqueous hydrogen peroxide solution. The mixture was stirred for 30 minutes, then poured into 50 ml of water and extracted with a chloride (3 x 100 ml). The combined extracts are dried over MgSO 4 and evaporated down. The residue was purified by means of a fast chimotorratil column, eluted with ethyl acetate / hexane / 1: 1 v / v, gradually increasing to 100% ethyl acetate) and yielding (4S) - (3 - / - / 2S) - 2- ( ^- ) SS-1-hydarksyrl- (3-pyrridyl) ethyl-7-pent-4-enol-4-propyloxazolidin-2-one (B) in the form of a solid, m.p. H2-11 ³ ° C (after recrystallization from tobenu / ²⁵ ^ "<oC_ Ο · ^ ^-136, 0 / EOOH c 0.311 / j NMR: 0.85 / 6H, dd, J» 7 Hz /, 2,15-2,7 / ^ H ^ 4.0-4.2 (2Hm), 4.3-4.55 (2H, m), 4.95-5.1 (3H, m), 5.65-5.9 / H, m, 7.25 -7.35 (lH, m /, 7.75-7.85 (lH, O, 8.5-8.65) 2H, O · / 111 / Oo of a solution of 5.76 g of B in 40 ol of methanol, chilled to 5 ° C, 3.65 ml of 30% w / w is added. a solution of sodium methoxide in methanol. The mixture is stirred for 15 minutes, then 10 ml of saturated aqueous ammonium chloride solution and 50 ml of ether are added. S is added to water to dissolve the precipitated inorganics and the mixture is extracted with ether (3 x 50 ml). The combined extracts are dried over MgSO 4 and evaporated down. The residue is purified by a flash column and eluted with ethyl acetate to give 3.245 g (2S / -2- (7SS) -h-hydroxy-1- (3-plryri) methyl / pent-methyl pent-4-enate / 0 / w Oil form: NMR: 2.3-2.6 (2H, m), 2.8-2.9 (1H, m (3.6) (3H, s), 4.95-5.1 µm) , 5.65-5.85 (µm), 7.25-7.35 (1H, m), 7.7-7.5 (Hm), 8.45-8.6 (2H, m).

/ iv / 50% of chilled content, 767 g of hydride in 50 ml of THF, a solution of 3.88 g of C in 10 ml of THF is added dropwise at such a rate as to keep the temperature below ¹⁰ ° C. etztnin ^ę month / a ^SIU at ⁵ ° C for 4 ^g odziny · Oodaje ^SIU 20 ml uouli then 10 ol saturated aqueous ro / solution of ammonium chloride and 10 ml of water. the mixture was extracted with ethyl acetate / 3 x 50 ml /. Połączrme the extracts are dried over MgSO 4 and evaporated down. The residue is purified by rapid chrimtorgafi-columnet, eluted with ethyl acetate, gradually added to mθthanol / ethyl acetate / 1: 9 oil (v / v) to obtain / lS · 2R / -2-Blliro-13 / p.-prydyl / -1 »3-arppandrl / D / in the amount of 2.69 g, in the form of an oil: NMR: 1.65-1.8 / lH, m /, 1.95-2.15 (2H, m), 3.15-3.45 (2H, m /, 4.4-4.5 (Hm), 4.75-5.0 / 3H, m /, 5.25 (lH, d, 3 = 7 Hz), 5.6-5.85 (lH, o), 7.3-7.4 (H, m), 7.65-7.7) 1h, m /, 8.4-8.5 (2H, o).

/ v / 2.91 g of p-toUnosilironic acid mono-dianl is added to the solution 2.68 g of O in 15 ml of 2 · 2-dimetronsilirone and the mixture is stirred for 16 hours. 10 ol oriethylamine is added and the mixture is partitioned between 50 ml of eoer and 20 ml of water. The organic layer is dried with MgSO 4 and evaporated down. The residue was purified by flash chromatography criumnovet, eluted with ethyl acetate / hexane (1: 1 v / v) to give 2.39 g (45.5 R) -5-aliiro-22.2-dimethyl-4. - / 3-plridyl / -1,3-0loStmπu / E / in the form of an oil: NOW: 1.53 / 3H, s /, 1.55 / 3H, s /, 1.6-1.75 / H, m /, 1.9-2.0 / H, m /, 2.3-2.5 / H, m /, 3.85-4.2 / 2H, m /, 4.9-5.0 / 2H , m /, 5.27 (H, d. 0 "3Hz /, 5.45-5.7 (m, 1"), 7.25-7.35 (H, m), 7.65-7.7 (Hm), 8.5-8.6 / 2H, o /.

/ vi / Ozone is passed through a solution of 530 mg / mol of aHt2 in 30 ml of metβnol, cooled to -78 ° C, until the solution turns blue. The mixture is purged with argon prior to the addition of 1.6 ol methyl sulfide. The mixture is then stirred at room temperature for 18 hours, after which it is concentrated under reduced pressure and reduced pressure. / is divided between 50 ol eier and 20 ml water. The organic layer is dried with MgSO 4 and evaporated down. The residue is purified on the rapid chromotoorat ϋ krilmπowet, eluted with a mixture of methanol and methylene chloride (5:95 oily (v / v) to give 2- (74S, 5R) -2,2-dimethyl? -4 / 3ppardc! yro (-1, d-oioxin-5-yl_yaeotβlehhy ^d (F) in the form of an oil: NMR: 1.53 (3H, s), 1.55 (3H, s), 2.15-2.4 (2H) m /, 2.85-2.95 (H, m), 3.8-3.85 (Hm), 4.25-4.35 (H, m), 5.28 (IH.d, 3 = 33h), 7.25-7.7 (2 µm, m), 8.5-8.6 (2H, m), 9.6 (1H, s).

163 045 / note: The optical purity is> 99% based on proton NMRt with the addition of / R / - / - / - 2,2,2-tnfluoro-1- / 9-anthryl / ethanol, the region is 2.7 -2.9 (delta), which shows 4 doublets at 2.77, 2.71, 2.82 and 2.85 (1H, CH-CHO).

(vn) Acetaldehyde (F) is converted into acid 4 (Z) -6- (74S, 5R) -2,2-dimethyl-4- (3-pyridin) - 25 - _- in

-1,3-dlok8an-5-yl) - eθSnna, showing Z cO _ / q -113.3 (EtOH, c 0.465) and NMR essentially the same as the recemic substance described in Example 1, with the above conversion being performed by the same way as described in example 1 part / v /.

Example XLVI1I '409 mg of p-toUuenosHooo acid monooodate are added to the solution while stirring, 570 mg of 4 (Z) -6-Z5,2-dematyl-4- (3-pytidyl) -1,3-dloxane-cis- S-yl) hexanoic acid and 568 mg of 2- (2-cy-Io-4-emylanoxy) 22-methylpyropaal in 5 ml of acetonitrile, and the mixture was stirred at 80 ° C for 18 hours. 40 ml of water and 4 ml of a 2M sodium hydroxide solution are added and washed with the ether mixture (2 x 20 ml). The aqueous phase is acidified with acetic acid and extracted with ethyl acetate (3 x 25 ml). The extracts are washed with saturated brine (2 x 15 ml), dried over MgSO 4, and evaporated. The gummy residue was purified by MPLC, eluted with ethyl acetate / hexane / acetic acid (70: 30: 1 v / v) to give 249 mg of the 4 (Z) -6-Z ~ / 2 ₁ 4 acid hemihydrate. , -JCl8 / - / - / 1- / y-aoJβno-m ~ mθtylpheloxy / -l-methylatyl / -43 / p-ptΓydo / o / -1,3-dSaOsantloyho7haaoθnowθgo in the form of white planes:

NMR? 1.48 (3H, s), 1.50 (3H, s), 1.57 (H, m), 1.72 (H, m), 2.09 (0.75H, s), 2.27) 4H, m /, 2.30 / 3H, s /, 2.43 (1H, m /, 4.02 (1H.mm 3-1Hz), 4.19 /H.dd, 3 = 11.1.5Hz /, 4.98 (1H, s), 5.18 (H, d, 3-2Hz), 5.25 (Hm). 5.41 (1H, m /, 5.77 (1H, b), 7.09 (Hd, 7.28 (3H, m), 7.57 (H, dm, 3 = 8Hz), 8.45) H, bs (8.51 / H, bd, 3.4Hz) rnikroannlysis: found C 68.0,

H 6.5, N 6.0%: for ε26 ^Η 3θ ^Ν 2θ5 · ° «5Η ₂ 0 the following was calculated: C 65.0, H 6.7, N 6.1%: m / e 451 / M + H / *.

The starting aldehyde is produced in the following way:

/ 1 / 14.0 g of anhydrous potassium carbonate are added, during meshenol, to a solution of 19.0 g of 2-broml-4-methylphenol and 27.7 g of ethyl 2-broeo-2-methylphenate in 80 ml of 2-butanone and the mixture is heated. reflux the mixture for 3 hours, then it is cooled to ambient temperature and added to 400 ml of water. The mixture is extracted with etseem / 1 x 300 ml, 2 x 150 ml /, the combined extracts are washed with 1M sodium oodolene solution / 2 x 100 ml /, water / 2 x 100 ml / and neural brine / 1 x 100 ml / , then dried over MgSO 4 and the solvent is evaporated off. The residual oily substance is distilled under reduced pressure to give 18.7 g of ethyl 2- (2-blomo-4-methylphenoxy) -2-methylphenolylate (A) as an oil with a temperature of ¹ 16 ~ ¹ 1 ⁸ ° C after ^d. ciemen ^ m ^{0 2} 66.10 spider NM! and ^1: 28 ^ ^3H, t / 3.7Hz / 1 ^ 60 / 6H, s /, 2.26 / 3H, s /, 4.26 / 2H, q, 3.7 Hz /, 6.78 (IH.d, 3.8Hz /, 6.96 (IH.dd, 3.8, 1.5Hz), 7.35 (IH.d, 3.1.5Hz / IU / e 318 / M + NHh / *.

/ 11 / 3.76 g of copper cyanide is inserted to a stirred solution of 10.54 g A in 20 ml of dimethyl ^l lfoemamidu, the part .mu.m ogezawa si.ę to reflux temperature / ^L ażni 0 ¹⁸ ° C / in rd ^ ^g at 4.5 hours.

After cooling, the residue is added with stirring to a solution containing ferric chloride, 12M hydrochloric acid and water in the ratio of 14 g: 3.5 ml: 55 ml, and stirring is continued for 30 minutes. The solution is extracted with dichloromethane (1 x 100 ml, 2 x 50 ml), the combined extracts are washed with water (3 x 50 ml), then dried over MgSO, and the solvent is removed in vacuo. The residue was purified by MPLC, eluted with 10% v / v. ethylacetates in hexane to give 7.01 g of ethyl 2- (2JtyIaπo-4-e-tttllf eoxy) -2-ethylpropionylate (B) as a colorless oil which slowly crystallizes when kept at 4 ° C and mp 54-56 ° Cj NMR: 1.24 (3H, t, 3 = 7 Hz), 1.65 (6H, s), 2.91 (3H, s), 4.23 (2H, q,

3.7 Hz /, 6.74 (lH, d, 3.9 Hz), 7.21 / H, m /, 7.35 / H, d. 3 &lt; 2Hz / j m / e 265 / M + NH4 / *.

(111) A solution of 2.47 g of B in 40 ml of dry toluene is soaked under argon and cooled to -70 ° C, and then it is added dropwise to a solution of 7.3 ml of 1.5M dl / nmutyl carbon hydride solution in toluene. Stirring is continued for 30 minutes at -70 ° C, during which time 2 ml of 10 sub / v / v solution are added. The mixture is heated to ambient temperature and the mixture is heated to ambient temperature. The solution is added to the loosely divided mixture of 50 ml of water with a lid, it is stirred for 2 hours and then dried over diatomaceous earth. They are separated into the organic phase and the aqueous phase is extracted with ether (2 x 75 ml). The combined organic phases are washed with saturated brine (2 x 40 ml), dried over MgSO, and evaporated. After lc / tszJzαoiu pezosta163 045 elk by MPLC. elution 10% v / v. Acetyl octane in hexane gives an oil which slowly crystallizes. After trituration with hexane and filtration, 600 mg of 2- (2-cyano-4-matylphenoxy-2-methylpropanone) are obtained, mp 60-64 ° C. NM?

2.31 (3H, s), 6.74 (H, d, 3.9 Hz), 7.26 (7.39 (1H, d, 3-2Hz), 9.83 (HH, s) m / e 221 / m * nh ₄ / *.

Example XLIX. In a similar manner to that described in Example XLVIII, starting from 2- / 2-cyJaoo-5-mθtyllfθoxne / -2nmithylpanal instead of 2- / 2-cyano-4-matyllphanoxy / '- / - netylpropanal and heating the mixture for 48 hours afterMast 18 hours, 4 / Z / -6- / / 2,4,5-ce9 / -2- / 1- / n-cyano-5-ιnenylpnooxy / -1-methyllβtyl / -4 - / - ppirdnyl / is produced -1,3-diex (5-n-yl-yhein-carbon) at 1 T% yield, as white foam] NMR: 1.49 (31, s), 1.52 (3H, s), 1.59 (1H, n) 1.73 (lH, m), 2.28 (4H, m), 2.36 (3H, s), 2.43 (lH.m), 4.03 (lH.dm, 3-1lHz), 4.20 (IH.dd, 3-11.1Hz /, 4.97 (lH, s) /, 5.17 / Hd, 3-2Hz /,

5.23 (1H.m), 5.41 (1H, m), 6.92 (1H.dd, 3-7.1Hz), 7.02 (H, a), 7.30 (1H.m) /, 7.36 (lH.d, 3-7 Hz), 7.57 (lH, n), 8.49 (2H, n): microannaysis: found: C 68.1, H 6.5, N 5, 9%] for C ₂ 6H3qN20 ₅ .0.5H ₂ ° / Ποζοπο: C 68.0, H 6.7, N 6.1% IU / e / M + H / *.

The necessary aldehyde ^ is obtained as follows:

/ i / By a procedure similar to that described in Example XLVIII / i /, but starting from 2- ^ 1 ^ ^ 5-methylphenol instead of 2-bromo-4-methylfinol and boiling for 18 hours instead of 3 hours, 2- / Ethyl 2-hh0ol-55-methylennoken / -2-methylethyldilphionate with a yield of 72%, in the form of a colorless oil] pH 109-11O ° C under pressure

0.66.10 ² Paj NMF? ^: 1.28 (3H, t, 3-7 Hz). 1..60 / 6H, s /, 2.26 / 3H, s /, 4.26 / 2H. q. 3 »7Hz /. 6.72 (2H, n). 7.21 (lH, d, 3.7Hz) m / e 274 (M + NH4) *.

/ 11 / Splilbim similar to that described in Example XLVIII / 11 /, but starting with 2- / 2- ^ 1 ^^ -5-nitylofβnlxy / -2-methylpropilniβne instead of / 2- / 2-bromo-4-methyliβnoken / - 2mmityloprn pionianu acetate 1 etlsując as solvent OMPU zamast dlmθtylofloιnamidu and heating, washing machine / ^p slaughter ioajęc ¹⁸ hours in ² °°° ^C. prepared ^SIU sutistancję c ^and EKL ^EFSA after otdparowaniu elcstra ^ s dlc llrofnatenowych ^h. This material is dissolved in 200 ml of ether and washed with water 3 x 50 ml. to remove OMPU. then dried over MgSO 4 and evaporated off. The residue was saved by the M MC route. 10% v / v eluted. ethyl acetate in hexane to give

Ethyl 2- (2-cyno-5-oitnylphnlk3y) -2-oethyleneprlpionate with an yield of 38% as a colorless oil: NM / 250 MHz. CDCl-i (: 1.24 (3M, 3-7 Hz), 1.67 (Ex. S), 2.33. / 31. s /, 4.24 / 2H,

Q. J-7HZ /. 6.60 / Hs /, 6.84 /lH.dm, 3 = 8 Hz /, 7.44 / H, d, 3 = 8 Hz / IU / e 265 / M + ₄ Nl / *.

/ lii / In a manner similar to that described in Example XLVIII / iii / but starting from ethyl 2- / 2-methylpropionylphenoxy / -2-methylpropionlaπ instead of 2- / 2-cyjaoo-4-oxyethylene / 2-mitylopropylpylate, 2- (2-c) ion-5-omethylienokey (-2-mitnlopΓlpaoβ1) yielded 28% as a crystalline solid, mp 57-59 ° C | NM ?: / 250 MHz. CDO ^ y: 1.53 / 6H, ^^. 2.34 (3H, s), 6.62 (Hs), 6.91 (1H, d, 3-8H). 7.47 (lH.d, 3-8 lz), 9.34 (lH, s, [mu] m / e 221 (M + NH ₄ ) +.

Example L. Using the method ^ Ι ^ ογη to that described in Example XLVIII. but starting from / - / 2in / jnlO-4mmirokeyfeook ^ y / -2-oatylpropenal with / - / 2iCyjθnl-4-mitnlofinoxy / - / - metnlopΓopjOjlu, the acid 4- / 2 / -6 - ^ / 2.4 is prepared. 5th s ^ J (l-^^ yjaol-4-oethoxyphenoxy) -1-methylthinol-4- (3-plridylol-1,3-dlox-5nyl-ketin). with a yield of 10%. mp. 130-140 ° C, NMR 1.46 (3H, s), 1.48 (31, s), 1.58 (1H, m), 1.72 (H, o). 2.26 / 4l, m /, 2.42 / lH, m /, 3.76 / 3H, n /, 4.03 3 1Πζ /, 4.20 / H, dd. 3-11, 1.5 Hz /. 4.97 (1H.s), 5.17 (Hd, 3 = 2 Hz), 5.24 (1H.m), 5.40 (1H.m), 6.93 (1H, d, 3 = 2.5 Hz). 7.02 µH _T dd.

3 - B. 2.5Hz /, 7.12 / H, d, 3-8Hz /. 7.30 (1H, n), 7.57 (1h, o), 8.50 (2H, m), microanneysis found: C 66.5. l 6.2. N 5, £% j for C26H30 ^N 206 onliisono: C 56.9, H 6.5. N 6.0% IU / e / M + H / *

The starting aldehyde is prepared by the following eplsobio:

/ 1/2 and 1 sodium olefinide solution is added with continued stirring to a solution of 9.4 g of 2-hydrocy-5-methoxynzaldehyde 1 5.37 g of hydroxylamine hydrochloride in 100 ml of molar. until 7. Stir the caissons for a further 20 minutes then added 1 niee / ^{E D} αoin 600 ml water. J ^p of cooling of about 4 ° C for ² hours cut. ^SIU filtered white ^precipitate was. washed with water 1 dried 1 yields 9.84 g of / -Hndroxy-5-net oxybenzalOoSnn ^π, u / A /

163 045 in the form of white crystals melting at ¹² 0 ° H.9- Cj NMR: 3.77 / 3H, s /, ^6, 70 /lH.d 3 ^- 2Hz /, 6.90 / 2H, m /, 7.47 (lH, s), 8.1.9 (lH.s). 9.39 / 1h ^, IU / e 1.68 / M + H / *.

(ii) A solution of 9.84 g of A in 50 ml of acetic anhydride is boiled for 6 hours. The mixture is allowed to stand overnight at ambient temperature and then added to a vigorously stirred ice-water mixture in the amount of 400 ml. After 1 hour, the solid formed was filtered off. About a solution of this substance in 50 ml of methanol is added while stirring with 150 ml of 2M sodium hydroxide solution. Stirring is continued for 1 hour. The resulting clear solution is washed with 50 ml of ether, acidified with 2M hydrochloric acid solution to pH 4, and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with 20 mL water, then 20 ml of saturated brine, dried over MgSOo · solvent is evaporated to give 783 g of 2-cyano-4-methoxyphenol / 6 / in the form of a white solid of melting ^a crusher ^tions 128 138 ° Cj NMR / 250 ^{^^^,} ^ CDCl / DreOOg / ^3, 66 / 3Η, 8Λ 6.86 / 3H, m / IU / £ ⁶⁷ / ^m + NH ^h / * / iii / To a solution of 745 mg 0 and 755 mg of 2-bromo-2-methylpropanal in 20 ml of tetrahydrofuran was added with stirring to 1.38 g of anhydrous potassium carbonate. The mixture was heated for 1 hour and then left overnight at ambient temperature. 20 ml of water are added and the mixture is extracted with ether (2 x 20 ml). The combined extracts are washed with water (2 x 10 ml), then with 10 ml of saturated brine and dried over MgSO ₄ . After evaporation of the solvent and purification of the residual oil by medium pressure chrumaroogarli (MPLC) and elution with 25% v / v. ethyl acetate in hexane yielded 677 mg of 2- (2-cyno-4-methoxyphenoxy) -2-methylpropanal as a colorless oil: NMR: 1.47 (6H, s), 3.80 (3H, s), 6.83 (1H.d, 3b9Hz), 7.03 (2H, m), 9.85 (1H, s (µm) e (M + NH ₄ ).

Example LI. A method of hydrolysis analogous to that described in Example 12 is followed, but starting with 4 / Z / -6 - / "/ 2,4,5-cιy / -2-tθn / ludllluoromθtyfou4- / 3-plr / dy / oU-1, 3dioxan-5- / lo_7 ^- meeyl hokseniαnu. After evaporation of the extracts of the acidified reaction wax, a pale yellow oil is obtained, which solidifies on rubbing with hexane. After recrystallization from an ethyl acetate / hexane mixture, the yield was 58%, the acid 4 (Z (-6) "(2.4. S-css) - ² -fn (ylddifilur rmmethyl-4- (3-pyridyl)) -1,3-dioxan-5-yl 7 * ¹ ® xene, m.p. 146-148 ° C | NMR: 1.34 (1H, m /, 1.64 (1H, m), 1.99 (3H, m), 2.23 (2H, m /, 3.96 (1H.bd, 3-1Hz)) , 4.13 µH.bd. 3 / lHz /, 5.09 / 3H, m /, 5.35 / lH, m /, 7.13 / lH, m /, 7.46 / 3Η, m /, 7.60 / 3H, m /, 8.51 / 2H, m / J microannaysis: found: C 65.4, Η 5.8, N 3.5%; calculated for C22H23NF2 / 4: C 65.5, Η 5.7, N 3.5%; m / e 404 / M + H / *.

The starting aeter is prepared as follows:

/ 1 / Roztwiir ^{1.0 g} ° ^{C J} C ^{d f} lf uoul ^{r l} nπy oocranf et lu ^y / ^y twurzun ^s own preferences spusotiam ^g M1i ^- dleton and ^a Bingham, 3. Org. Boor. 1980, 45, 2883 / in 15 ml of dry toluene is stirred under argon and cooled to -70 ^° C, then 3.5 ml of a 1.5 M solution of dilzobutylgyl hydride in toluene are added dropwise over 15 minutes. Stirring is carried out for 1 hour at -70 ° C, during which time 1 ml of mK 2 R 2 ol is added. The solution is allowed to warm to ambient temperature and a vigorously stirred ice-water mixture is added. After stirring for a further 2 hours, the mixture was filtered through diatomaceous earth and separated. The aqueous phase is extracted with EtOAc (3 x 25 ml), the combined organic phase is washed with saturated brine (2 x 20 ml) then dried over MgSO 4 and evaporated to give Hi.

After MPLC, a reduction of 20% v / v. 760 mg of a colorless oil (A) is obtained, which, as NMR, is a mixture of (oC-dlfluoultn / ylaJcera-ahydrate and its corresponding hydrate and hemiacetal).

/ 11 / A method similar to that described in Example 12 / IV / but using a mixture of al-eh / -u and its derivatives A instead of hakaallumacetone sesquihydrate and using 60% v / v. ethyl acetate in hexane as eluent during Jhrumaroufine purification, prepared in 31% yield 4 (Z) -6- / 72,45-cιζ / -2-1 tθπ (lodll luornimtyl) -3- / 3-pyridine-1 , Methyl 3-dlukyαn-5-yl-7hθkytnytanate in the form of a waxy solid: NMR: 1.30 (1H, m /, 1.54 (1H, m), 1.98 (3Η), 2.20 / 2H, m /, 3.57 (3H, s), 3.97 (1H.mrn, 0 = 11Hz). 4.14 (1H, d, 3 µlHz), 5.08 (3H,, w), 5.31 (1H, m), 7.33 (1H, m), 7.47 (3H, m), 7.61 (SH. M), 8.49 (1H, d, 3.1 Hz), 8.54 (1H, dd, 3 = 4.1Hz (im / e 4.1S (M + H) *.

P r z / k e - LII. By the method of zJliunπya -o described in Provo / Ołr-zit T; gels using as aldeh / d 2-met / lo-2- / 2 amθt yUo8ullonylotθno0sy / propanal, in / twirza with s-y''jjnuyJl? 29%

163 045 // Z (415-cis (-2-) - methyl-1- (4-methyl-8-sulfonyl-phanoxy) -atyl) -4- (3-pyridyl) -1,3-dioxane-5-yl) -haxanoic acid, in the form of oil: NMR: 1.6 (6H, s), 1.7-2.6 (7H, m /, 3.2 (3H, s),

4.0-4.25 (21, m), 5.1 (1H, a), 5.2-5.5 (3H, m), 7.1-8.0 (6H, m), 8. 5-8.6 (2H, -).

The necessary aldahide is prepared starting from 2- (methylthio) fanol in an analogous manner to that described in Example 16 for the preparation of 2-methylk-2- / 4-π> atllosulkonylphanoxy / propanal. 2-methyl- 2 -methylsulfonylphanoxy (propanal) is prepared as a solid in 51% yield) from carboxylate: (NMR: 1.55 (6H, s), 3.25 (3H, s), 6.85- 7.55 / 3H, m /, 8.0-8.5 / lH, - /, 9.85 / lH, s /, with the release of the following acyclic compounds: a / 2 - only-2- / 2- - only (fnooxy) atyl propionate in the form of oil with a yield of 38%, from lanol: NMR: 1.25 (31, t, 3 = 7 Hz), 1.6 (6H, s), 2.4 (3H, s) , 4.25 (2H, q, 3 = 7Hh), 6.7-7.2 / 4H, - / i (b) 2---2- with an yield of 89%, z / a /: NMR: 1.25 (3H, t, 3.7 Hz), 1.7 (6H, s), 3.25 (3H, s), 4.3 / 2H, q . 0-7 Hz), 6.9-7.55 (3H, -), 7.95-8.05 (1H, -).

Examples LIII-LH. By the method described in Example I, but using 2 - ethylk-2- / 2 - atllotkofθkoxy / -pkopankl 1 2 - tylk-2- / 4 - atylthotnoxy / propanal, respectively, the following are prepared:

Example LIII: acid 4 / Z / -6- / / 2,4, n-cls / -2- / 1-mβtyl-1- / 2-ιtθlykotiofskoxy / phtylk / -4-33-plrylyfo / -1, 3- dioJsan-11lClOh / hθxβ in the form of a solid in 45% yield: NMR: 1.45 (31 ° C). 1.5 (3H, s), 1.55 (2H, m), 2.2-2.5 (8H.-/, 4.0-4.25 / 21, - /, 5.0 / 1H, s /, 5.1-5.5 (31, m) (7.0-7.7 (6H, rn), 8.5-8.6 (2H, m).

Example LIV .: acid 4 / Z / -6 - // 2,4.5-cis / -2- / l-mθtyfο-1- / 4- «θιyootlofβkoksl / phtylk / -4- / 3-pllydyko / -l, d -cooxane-5-clo-7hθSJθne, in the form of a solid and with a yield of 26%: NMR: 1.35 (3H, s), 1.4 (3H, s), 1.6-1.8 / 2H, -. 2, 2-2.5 / 8l, m /, 3.95-4.25 / 2H, m /, 4.75 / ΙΗ4 /, 5.1-5.5 / 3h, - /, 6.9-7 , 75 (5H, m /, 8.5-6.6 (2H, m).

The initial aldali ^ y ^^ t ^^ r / a is analogous to the method of kpisanagk in the 16th method ^^ tw ^ i- / anu 2-maylo-2- / 4-ma0ylooulphonycophonoxl / propanal:

/ a / 2l-θtylk-2- / 2 - ethylkthotenkOoy / prkpanal, separated in the form of olajut NMR: 1.45 / δΗ ^ /,

2.4 (3H, s /, 6.7-7.2 / 4H, - /, 9.9 / 1h, b / j 53% yield, for 2-atyl-2- (2-mθtlloOlotθnokay) proplonaan raduction atyl 1 / b / 2 - eJylo-2- / 4 - tylkOlofθnoOol / prkpanal, separated as an oil: NMR: 1.4 / 6H, s /, 2.45 / 31.8/, 6.75-7.25 (4H, -), 9.85 (1H, s).

Example LV. By a method analogous to that described in example I, ala otksuJac As 2-tocofnkoxiban / aldahide aldahide, the acid 4 / Z / -6- / ^- / 2.4.5 "Ci8 / 14l / 3-piΓydllk / ll; -l- is prepared. flffecoxlίfnofko / -l, 3-αlof: ooJ'-5-ylk_7haOoankwy, in the form of a solid / yield 26% j NMR: 1.7-1.9 / 21, -, 2.2-2.5 / 51, - /, 4.1-4.3 (2H, m /, 5.2-5.5 (3H, -), 6.15 (1H, -), 7.1-7.9 (IUm), 8, 45-8.6 / 21, - /.

2-phosphotocobenzaldehyde is prepared by a known method from 21 -fluocobenzaldehyde and thiophanol.

Examples LVI-LVII. By a method analogous to that described in example I, ala starting from 2l-βtylkl2 - / - nltrt> 4-methoxyphenkcal / propanal and 2-mθtolok22 / 2-aθtll / -6-nltkotnkoxl / prkl panel, respectively, is prepared:

Example LVI. Acid 4 / Z / -6l / "/ 2,4, n-cis / -2- / 1-aθlyko / -l- / 2-nctrom4amooxyfskol / / θtykol --- / 3-plridyl / -l, 3kdloas -yl) (0βk8θkwa in the form of a solid, with a yield of 10% NMR: 1.35 (61, s), 1.45-1.7 (2L, m), 2.1-2.4 (5H, m) , 3.75 (31.a, 3.85-4.1 (2H, m), 4.75 (ΐΗ4), 5.0-5.4 (3H, m), 6.9-7. 55 (5H, -), 8.4-8.5 (2H, m).

Example LVII. Acid 4-Z - / - 6- / 7 ^ « ⁴ · 5-cis / -2- / 1-matyl-1- / 2-mati1o-6-s1-throienoxy / atllk / -4- / 3-ρilydllk / -l , 3-D10san-5-yl27heOSanil as a solid (7% yield NMR: 1.25 (31, s), 1.3 (3H.E), 1.45-1.65 (2H). m /, 2.05-2.4 / 8H, -, 3.8-4.05 (2H, -), 4.7 (1H, a), 5.0-5.5 / 31, -, 6 , 95-7.5 (5H, -), 8.35-8.5 (2H, -,

The new aldahydes are analogous to the kploanagk in the example of the 12th method of producing 2-methyl-2- / 4-mbtyiosulfonyo ctnni:> k9l / Drϋpanalu:

/ a / 2-me a olokl-12-ni th ropanal, iydziflknl in the form of an ovaline oil: NMR: 1.45 / 61, s /, 3.6 / 3H, o /, 6.9-7.3 (3H, m /, 9.85 (lH.s/), with an output of 41%, for the raduction of 2-me a yl ^ - ^ nnt t ro-4-aa o xsy a nnok sy / atylate propion, product / onago in the form of oil and NMR:

1.3 (3H, t 3 = 7Hz), 1.6 (61, s), 3.8 (3H, s), 4.25 (21, q, 3 = 77h), 7.0-7.3 / 3H, m /, / yield carrier30

163,045 cut 8%, by alkylation of 4-methoxy-2-nitrophanoloxol and (b) 2-methyl-2- (2-methyl-6-nitrophyloxy) propanel, isolated as yellow oil: NMR:

1.35 (6H, s), 2.3 (3H, s), 7.1-7.6 (3H, m), 9.85 (1H, s), with a yield of 65%, by reduction

Ethyl 2-meey1ο-2- / 2-ι-ethyl-6-nitrnfernxypropionate, prepared as an oil: NMR:

1.35 (3H, t, 3 = 7Hz), 1.5 (6H, s), 2.3 (3H, s ⁾ , 4.25 (2H, q, 3 = 7Hz), 7.05-7, 55 (3H, m /), 8% yield, for the alkyl 2-methyl-6-nitroOenol.

Example LVIII. The acid 4 / Z / -6 - / "/ 2,4,5-cSs / -2- / 2-aynzilylOanyl / - is prepared by a method similar to that described in Example 1, but using 2-ben (lylbn / aldθhydrate as aldehyde) 4- (3-pl -ddyl) -1,3-dloxane-5-yl-7-hexylene in the form of a solid in 64% yield: NMR: 1.15-1.45 (2H, m /, 1.85-2.2 / 5H) m /, 3.6-3.9 / 2H, m /, 4.7-5.3 / 3H, m /, 5.55 / Hm /, 6.8-7.65 / UH, · / 8.05-8.2 (2H, m).

2-bβn / lylbenzaldehyde is produced as a solid with an yield of 82% NMR:

7.4-8.1 (9H, m /, 10.05 (1H, s), by oxidation with chloride s / c // oilwy / dimethyl ^os ul ^o otl.ene ^k at -50 ° C ^d about ambient 2- / © <h ^{y l} drlks bθnzylo / benzylowago alcohol produced as a solid in 26% wydaanościę j NMR 2.95 / H, br s /, 4.45-4.65 / 2H, m /, 6.05 (1H, s), 7.2-7.4 (9H, m) by reduction of the acid with 2-benzoylb / loβ10carbonate with linohydride.

Examples of LIX-LX. Analogicnnym method to that described in Example XXIII, but starting £ ^d powiθdniβg thien ^ ldatiycJu ^of the formula ^R-CHO, prepared näätä t ^{o p} u ^j ^ ECE conjunction zlki:

Example LIX. Acid 4 / Z / -6- / / 2,4,5-cis / -2- / 1-mmethyl-1-O-tnylthio / 44- ( ^3- pythridium) - 1,3-d: 1.oSsnn55-yl / hθk8nl in the form of a colorless solid, mp 118-120 ° C: NMR: 1.32 (6H, s) 1.65 (2H, m /, 2.31 (5H, m /), 3.90 (1H, d), 4.18 (1H, d), 4.55 (1H, s), 5.00 (!, d), 5.22 (1H, m), 5.40 (H) , m /, 5.70 (Hm /, 7.28 / 4H, m /, 7.53 / 2H, m /, 7.62 (1H, d /, 6.5 ⁰ / 2H, ^m / e ⁴²⁸ ) M + N / j ^ ⁺ yield of ^63%, the compound output ^y - 2-mθtylo-2- / ^o enylot 10 / / prnpanal.

Example LX. Acid 4 / Z / -6- / 7 ² · 4,5-cis / -2- / 1-methylool - ^ - Oluorophanylono / ethyl / -4- (3-ptridyl) -1,3-dloxane-5 -ll / h7 ^hθ kselooy, as a colorless solid, mp 109-III ° C NMR: 1.33 / 6H, s / 1.64 HMA ^ ^2, 34 ^3, 90 / H, m ^/, 4 ^, 18 (H, m), 4.56 (1H, s), 5.02 (1H, d), 5.31 (2H, m), 6.94 (2H, m), 7.35 / H, m /, 7.55 / 3H, m /, 8.52 / 2Hm / ^j m / e ⁴⁴⁴ / MH / j * ^{Yield 61%,} the compound output ^ and about ¹ - about ² -MAT ^yl 2- / 4-f luoro ⁰ enyl n- / / propanal.

Input benzaldehydes are prepared in a manner similar to that described in Example I (vn) they show the following properties:

/ a / 2-methylOl-2 / 0eyylthio / propanal, produced in the form of an oil with a yield of 40% NMIR: 1.25 / βΜ /, ^7.25 / 51- ^ m /, ^9.28 / 1h, s / µm / ^{e 194} / M + NH ₄ / * j · wytworzm ^{1 of} enylotiolu ^{yl, 1 h} -dic lotl-2-hldroksy-2-matyloplopanu and / b / 2-e is yloo2- / 4 for f ro 0 eny lo t o / p &lt; pena !, prepared from 4-fHoro-phenyl thiol and 1,1-dichloro-2-hydroxy-2-methylpropane with a yield of 14% as NMIR oil: 1.31 / 6H, s /, 6.99 (2H, ra), 7.36 (2H, raa, 9.28 (1H, s); ra / e 216 / HłH !! / *.

Example LXI. The acid catalyzed aldehyde / ketone exchange teacon described in any of Examples XXIII-LX can also be performed using 4 (Z) -6- (2,2-diethIII-4- (3-pptyldyl) -1,33 acid. -dlo / yac-ci8-5-yloxy / described in / Γ / lk / d / and XIV / instead of the 2,2-dimethyl derivative / compound / A / described in part / v / example 1 j. Usually very similar are obtained. oyda / nlści / wią / ków ow ^ or / a I.

163 045

Formula 3

J63 045

Formula 6

163 045

COR '

Formula 9

163 045

Formula 13

163 045

\

(ii) ν '

Pattern 1 Sir 1 (iii)

Ψ

(n = 1) Formula 6

Scheme 1 p?

163 045

Scheme 2 i

Scheme 2 page 2

163 045

Scheme 3 su /

163 045

esterification or sulfonamidation

Scheme 4

Publishing Department of the UP RP. Circulation of 90 copies

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Claims (3)

Patent Claims 1 2 4 / ^ CC / akkylntowego, / 2-6C / akennytnrtic or directly imprisoning the pteriQ 1 Q, R denote the hyOotxyltoo group, physiothermic Orepositive alcohol or the group / l-4C / akkantsulftaαyiOtoę or their pharmaceutically characterized in that the 1'-dioxane of the formula - in which JeOen with Ra 1 Rb trnacra etom hydrogen, a methyl or ethyl group and the second a methyl or ethyl group, where the reaction takes place in the form of R, CHO or Jegt. nodolaaul acetal or hemiacetal, in the presence of an acid, then the required o ^^ compound is required (tm 1, the compound of formula 1 reacts with r raoaOe or acidic Oo β-shield acid physiotogically Ooppable Jtn or other known yeαkcJi formation oo !!, and When an optically active form of the compound of formula 1 is required. One of the above processes is carried out using an optically active starting compound, or the racemic form of the compound of formula 1 is resolved, wherein in the above-mentioned formulas R, R, R, n , Y, A and X are as defined above. 1 2 3 1 12 or tnifluoΓmmθtytooa, or R is a group of formula q, A, Qi, where Q and Q are aromatic moieties, JeOen is benzene, and the second is benzene or pyrroline, each of these groups may be lvendualnil substituted halogen, cyano, nitrile, (lC) alky, (l-0;) altaknyt or tnfthymethyl, where A is thio, oulfdnytoo, oulfonyl, kαrbt-dyl, carbamolltoy, mimintyl, tetymethyl / akkilatowa, oxy / 1 2 t / R and R independent are an alkylene group or together form an alkylene group such that 12 4 R and R together revolve --9 carbon atoms, R denotes a group of cydΓtconlwę, physiologically Oacceptable alcoholic group or the group / i44C / alk8tounifoneιnttowa luD flax pharmaceutically OtpιJ8ZCzaynyyC goals, characterized by that re 1,3-dtaxad t Sea -, in which trdayrę and Rb is hydrogen, methyl or ethyl, and Orugi methyl or ethyl group, from ^p (^ (^ 6i them ^ę reaction on the bearing alde ^ t CJU formula ^r \ cHO i.ub ^j ^ agt in dol / au ^acetal ]. or [semitatal, in the presence of an acid, and then a compound t of formula 1 is required, the compound t of formula 1 reacts with a reaction of raoOę or a koaolm of physiotogically releases an ion or other known salt formation reaction, and it is optically required by The active form of the compound of formula I, the above primes, leads to the formation of an optically active compound in the form of a compound of formula 1, where in the above-mentioned formulas R, R, R is dissolved the racemic form of the compound of formula 1. , η, Y, O and X have the above meanings, 1. Ptosób wytweraanaa towych t ° ctodnycn of 1,3-tioasanoalktnoweto of wtores 1, wherein n is 1 LSB całktwitę 2, X is a hydroxyl group lsb / l-4C / alkt of ^a ltoę ^{y and γ} traacra ru ^{g PE} metylenttao oin lenoo ^{y n} and ^{a y-slb} at lenoo ^{E 1} and ^a is rs ^{g PE} / 1-60 / ali anlanonę, and further 2 1 w, R denotes a nephrite group, R trnacra a nephrite group, lnθndualnle containing 1 or 2 substituents, such as halogens, cyano, nitro, / 1-CC / alky, / 1-CC / slate 2, the process for preparing 1,3odloksataalkennlθgo acid derivatives of the formula 1, TDO yni ^ n is the integer 1 or 2, X is hydrogen, C ^ O ^^ bast / or l-CC / ^{akkoaenltnę, γ g} is ru ^pe me tyllatt ^{k 6y,} pour ^y lenoo ^{by E l} etyilenowę ^{ub, N} ru trnacra ^{g PE} / l ^ ec / ks ^ entl 2 3 partially lluorow / ancc, albt A trnacra bazposreOnnation r R, 2 - 1 3 2 3 a / R is hydrogen, R tmracra grp t with the formula R 10, where R t trnacra grp phenyl is substituted with such a substituent. Like / 1-C / alkite, / 1-CZ / actoxy, / 2-5C / alkanyi ltwa, / 1-4C / alkilttiti / 1C / akkitoeulfmite, / 1-CC / aknylsulfnnytovll / 2-SC / alkantnium, carbethylene yl-CC / βikaOny / -cartdnytowa, / A- / l-CC / saktla / karbyαtitooa, / lC / alkantiltαmlntw / or / l ^ C / alkitic, substituted grspa / l-CC / actoxy, cyano, carbtk / ylooe or / yl-CC / alkaOny // abtonyl, and the lldylo group / may contain Orugn substituent such as / l-4C / elkίtow /, / l-CC-aβltak8ytooa, tmi ltormmθtytooα, altr! ^ w / l cyano or yaltrtwya , or R trdayrα a thienyt or luryi group, ewβnduainle with 1 or 2 substituents for selected r groups, including a halogen atom, a group / 1-4C / alkyl, nitric and cyanth ^^, O tznayra group / ^ C / akkilnt, tksy / l-6C / alkllatnwę or / 2-60 / alaαaylentoę, with the crym of Ot three carbon atoms of each group may be ^ Ι ^ ι ^^ ι or 3. The source of the synthesis of the lower acid 1,3-disxanalconium acid of the formula 1, in which n is an integer 1 or 2, X is hydrogen, a hydroxyl group or / -4CC / algok9 Iowa history, Y represents an mθlylenook9y, wlawlθnowę or ethylene, means a / L iC / elk ile2 1 1 aooίj _l R orazcra hydrogen, R is pθntafludroetygowę either each of R and R ¹ is a ^g roup ^E t nif ^l UDR ^ d ^^^ ^{yl Goe, R4} is hydro ^{ę g} roup s ^{Looe k, f} and JoJgicznie dopu ^ CCE! The other alcohol residue or the / 1 -CcValkagzuulfonyml group or their pharmaceutically acceptable salts, characterized in that the 1'-dioxane of the formula 5, wherein one of Ra and Rb is a hydrogen atom, a methyl or ethyl group and the other a methyl or ethyl group, subjected ^J e ^SIU reacted with excess of an aldehyde of mom ^R .ch ° l.ub J ^ o ^ wodzimu l.ub itacetalu acetal in the presence of an acid and, when it is desired salt of the compound of formula 1, I ^ nk of the formula 1 is reacted with a base or acid to provide Ję fi When an optically active form of the compound of formula 1 is required. is the form of the compound of formula 1, where in the above-mentioned formulas R, R, R, η, Y, A and X have equal meanings. «*«